Sickle Cell Disease Subjects Have a Distinct Abnormal Autonomic Phenotype Characterized by Peripheral Vasoconstriction With Blunted Cardiac Response to Head-Up Tilt

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

Mental stress causes vasoconstriction in subjects with sickle cell disease and in normal controls

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

Nitric oxide, vasodilation and the red blood cell.

International audienceSince the identification of the elusive endothelium-derived relaxing factor as nitric oxide (NO), much attention has been devoted to understanding its physiological effects. NO is a free radical with many roles, and owing to its neutral charge and high diffusion capacity, it appears NO is involved in every mammalian biological system. Most attention has been focused on the NO generating pathways within the endothelium; however, the recent discovery of a NO synthase (NOS)-like enzyme residing in red blood cells (RBC) has increased our understanding of the blood flow and oxygen delivery modulation by RBC. In the present review, pathways of NO generation are summarized, with attention to those residing within RBC. While the bioactivity of RBC-derived NO is still debated due to its generation within proximity of NO scavengers, current theories for NO export from RBC are explored, which are supported by recent findings demonstrating an extracellular response to RBC-derived NO. The importance of NO in the active regulation of RBC deformability is discussed in the context of the subsequent effects on blood fluidity, and the complex interplay between blood rheology and NO are summarized. This review provides a summary of recent advances in understanding the role played by RBC in NO equilibrium and vascular regulation

The role of blood rheology in sickle cell disease

International audienceStudies performed in the last decades have highlighted the need to better understand the contribution of the endothelium, vascular function, oxidative stress, inflammation, coagulation, hemolysis and vascular adhesion mechanisms to the pathophysiology of acute vaso-occlusive like events and chronic organ damages in sickle cell disease (SCD). Although SCD is a hemorheological disease, a few works focused on the contribution of blood viscosity, plasma viscosity, red blood cell deformability and aggregation in the pathophysiology of SCD. After a brief description of basic hemorheology, the present review focuses on the role of the hemorheological abnormalities in the causation of several SCD complications, mainly in sickle cell anemia and hemoglobin (Hb) SC disease. Several genetic and cellular modulators of blood rheology in SCD are discussed, as well as unresolved questions and perspectives