Vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD) and occurs when deoxygenated sickled red blood cells occlude the microvasculature. Any stimulus, such as mental stress, which ...decreases microvascular blood flow will increase the likelihood of red cell entrapment resulting in local vaso-occlusion and progression to VOC. Neurally mediated vasoconstriction might be the physiological link between crisis triggers and vaso-occlusion. In this study, we determined the effect of mental stress on microvascular blood flow and autonomic nervous system reactivity. Sickle cell patients and controls performed mentally stressful tasks, including a memory task, conflict test and pain anticipation test. Blood flow was measured using photoplethysmography, autonomic reactivity was derived from electrocardiography and perceived stress was measured by the State-Trait Anxiety Inventory questionnaire. Stress tasks induced a significant decrease in microvascular blood flow, parasympathetic withdrawal and sympathetic activation in all subjects. Of the various tests, pain anticipation caused the highest degree of vasoconstriction. The magnitude of vasoconstriction, sympathetic activation and perceived stress was greater during the Stroop conflict test than during the N-back memory test, indicating the relationship between magnitude of experimental stress and degree of regional vasoconstriction. Baseline anxiety had a significant effect on the vasoconstrictive response in sickle cell subjects but not in controls. In conclusion, mental stress caused vasoconstriction and autonomic nervous system reactivity in all subjects. Although the pattern of responses was not significantly different between the two groups, the consequences of vasoconstriction can be quite significant in SCD because of the resultant entrapment of sickle cells in the microvasculature. This suggests that mental stress can precipitate a VOC in SCD by causing neural-mediated vasoconstriction.
Recent studies have shown that individuals with sickle cell disease (SCD) exhibit greater vasoconstriction responses to physical autonomic stressors, such as heat pain and cold pain than normal ...individuals, but this is not the case for mental stress (MTS). We sought to determine whether this anomalous finding for MTS is related to inter-group differences in baseline cardiac and vascular autonomic function. Fifteen subjects with SCD and 15 healthy volunteers participated in three MTS tasks: N-back, Stroop, and pain anticipation (PA). R–R interval (RRI), arterial blood pressure and finger photoplethysmogram (PPG) were continuously monitored before and during these MTS tasks. The magnitude of vasoconstriction was quantified using change in PPG amplitude (PPGa) from the baseline period. To represent basal autonomic function, we assessed both cardiac and vascular arms of the baroreflex during the baseline period. Cardiac baroreflex sensitivity (BRSc) was estimated by applying both the “sequence” and “spectral” techniques to beat-to-beat measurements of systolic blood pressure and RRIs. The vascular baroreflex sensitivity (BRSv) was quantified using the same approaches, modified for application to beat-to-beat diastolic blood pressure and PPGa measurements. Baseline BRSc was not different between SCD and non-SCD subjects, was not correlated with BRSv, and was not associated with the vasoconstriction responses to MTS tasks. BRSv in both groups was correlated with mean PPGa, and since both baseline PPGa and BRSv were lower in SCD, these results suggested that the SCD subjects were in a basal state of higher sympathetically mediated vascular tone. In both groups, baseline BRSv was positively correlated with the vasoconstriction responses to N-back, Stroop, and PA. After adjusting for differences in BRSv within and between groups, we found no difference in the vasoconstriction responses to all three mental tasks between SCD and non-SCD subjects. The implications of these findings are significant in subjects with SCD since vasoconstriction reduces microvascular flow and prolongs capillary transit time, increasing the likelihood for vaso-occlusive crisis (VOC) to be triggered by exposure to stressful events.
In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, ...predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects. Percent increase in heart rate from baseline was used to quantify cardiac ANS response, while percent decrease in PPG amplitude represented degree of peripheral vasoconstriction. After employing cluster analysis to determine threshold levels, the HUT responses were classified into four phenotypes: (CP) increased heart rate and peripheral vasoconstriction; (C) increased heart rate only; (P) peripheral vasoconstriction only; and (ST) subthreshold cardiac and peripheral vascular responses. Multinomial logistic regression (MLR) was used to relate these phenotypic responses to various parameters representing blood properties and baseline cardiovascular activity. The most common phenotypic response, CP, was found in 82% of non-SCD subjects, including those with chronic anemia. In contrast, 70% of SCD subjects responded abnormally to HUT: C-phenotype = 22%, P-phenotype = 37%, or ST-phenotype = 11%. MLR revealed that the HUT phenotypes were significantly associated with baseline cardiac parasympathetic activity, baseline peripheral vascular variability, hemoglobin level and SCD diagnosis. Low parasympathetic activity at baseline dramatically increased the probability of belonging to the P-phenotype in SCD subjects, even after adjusting for hemoglobin level, suggesting a characteristic autonomic dysfunction that is independent of anemia. Further analysis using a mathematical model of heart rate variability revealed that the low parasympathetic activity in P-phenotype SCD subjects was due to impaired respiratory-cardiac coupling rather than reduced cardiac baroreflex sensitivity. By having strong peripheral vasoconstriction without compensatory cardiac responses, P-phenotype subjects may be at increased risk for vaso-occlusive crisis. The classification of autonomic phenotypes based on HUT response may have potential use for guiding therapeutic interventions to alleviate the risk of adverse outcomes in SCD.
Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells ...that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.
Splenic iron decreased whereas liver iron was stable during luspatercept therapy in some individuals with thalassemia. This suggests a reduction of ineffective erythropoiesis changes the organ ...distribution of iron and demonstrates that liver iron concentration alone may not accurately reflect total body iron content. This article describes data from subjects enrolled in BELIEVE (NCT02604433) and BEYOND (NCT03342404).
Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate ...vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.
Introduction: Sickle cell disease (SCD) is characterized by microvascular occlusion from sickled red blood cells that can develop into full-blown vaso-occlusive crisis. We hypothesize that abnormal ...autonomic function plays a role in promoting microvascular occlusion in SCD. Head-up tilt (HUT) evokes a strong sympathetic response to the transient drop in blood pressure resulting from blood pooling in the lower extremities. Baroreflex regulation leads to heart rate (HR) increase and peripheral vasoconstriction. In this study, we subjected control and SCD subjects to the HUT test to assess their autonomic response.
Objective: To evaluate the autonomic response and determine the relative contributions of the cardiac and peripheral vascular responses to HUT in SCD compared to control subjects.
Experimental Protocols: 22 SCD and 17 control (healthy and sickle cell trait) subjects were recruited at Children's Hospital Los Angeles. Each subject laid supine on the tilt table for 5 minutes prior to being tilted up to 70° for 7 minutes, and subsequently returned to supine. Electrocardiogram, respiration, continuous blood pressure and photoplethysmograph (PPG) were measured continuously throughout the protocol. PPG amplitude was taken to represent peripheral blood flow (PBF) since reductions in PPG amplitude reflect vasoconstriction.
Analysis: Mean systolic blood pressure (SBP), HR and PBF were calculated over 2 minutes under baseline and HUT conditions. In HUT, we analyzed the physiological responses following 3 minutes of stabilization. Heart rate variability indices: high frequency power (HFP) and low-to-high ratio (LHR), reflecting parasympathetic activity and sympatho-vagal balance respectively, were also computed. Percent change from baseline of all parameters were computed to assess the tilt response after adjusting for their baseline values.
Results: There was not a significant change in SBP from baseline to HUT across all subjects. To maintain blood pressure, the response to HUT was categorized into 3 groups: 1) those who had increased HR (>15%) AND decreased PBF (>20%) from baseline, 2) those who only had increased HR, and 3) those who only had decreased PBF (Fig.1). While Group 1 and 2 responses were found in both controls and SCD, Group 3 responses consisted only of SCD subjects (Table 1). Although mean HR at baseline was not different from the other two groups, we found that HFP of Group 3 was lower compared to Group 1 (p = 0.0007) and Group 2 (p = 0.0396), while Group 3 LHR was higher than Group 1 (p = 0.0020).
Discussion & Conclusions: HUT is standard and well-recognized assessment of the autonomic response to transient drop in blood pressure. While most subjects maintained their SBP by increasing both HR and peripheral resistance, a subset of SCD subjects responded to HUT via only peripheral vasoconstriction. Moreover, these SCD subjects had significantly lower parasympathetic HR modulation at baseline as reflected by lower HFP and higher LHR, an index of sympatho-vagal balance. The findings suggest that baroreflex control of heart rate during HUT in this subset of SCD subjects was blunted due to low vagal and high cardiac sympathetic tone, whereas baroreflex control of peripheral vascular resistance remained relatively intact. These data provide further evidence that there is significant autonomic dysfunction in some patients with SCD. This hypersensitivity to vasoconstriction would decrease microvascular flow and would likely lead to vaso-occlusion. We speculate that this subset of SCD subjects may also be the most vulnerable to reduced PBF and thus VOC during orthostatic stress.
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No relevant conflicts of interest to declare.
Alpha thalassemia is a hemoglobinopathy due to decreased production of the α‐globin protein from loss of up to four α‐globin genes, with one or two missing in the trait phenotype. Individuals with ...sickle cell disease who co‐inherit the loss of one or two α‐globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α‐globin gene deletions affect sickle red cell deformability, the α‐globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α‐globin due to α‐thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow‐mediated dilation and microvascular post‐occlusive reactive hyperemia in 27 human subjects (15 missing one or two α‐globin genes and 12 healthy controls). Flow‐mediated dilation was significantly higher in subjects with α‐trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α‐globin gene status. This may explain the beneficial effect of α‐globin gene loss in sickle cell disease and suggests that α‐globin gene status may play a role in other vascular diseases.
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