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

Abstract

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.

Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

“…In the few subjects who had a repeat study, these vasoreactivity trends were reproducible. In fact, an autonomic vasoconstriction reactivity signature that is inherent to the individual appears to be present, as further evidenced in our experiments with autonomic tilt table testing [55].…”

“…Thus, the blood pressure normalizes due to the adaptive autonomic responses. Out of the 66 subjects (27 SCD, 13 anemic and 26 non-anemic controls) who were subjected to HUT testing, only 30% of SCD subjects had a normal response (tachycardia + vasoconstriction; Figure 5) [55]. All subjects, except for one, who responded with only peripheral vasoconstriction had SCD.…”

Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease

“…Consistent with this finding, Willen et al 16 showed no significant association between low mean nocturnal SpO 2 and incidence of VOC in the SAC participants studied here. On the other hand, we 5,7,8,24,25 and others 26‐29 have shown significant dysautonomia in SCD. Therefore, we examined measures of cardiac ANS balance (LHR, RMSSD) but found no association with VOC rate (modesl 8‐9 Table S2).…”

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

“…Of note, impaired CA (226–228) and reduced CVR (229, 230), have also been observed following sympathetic stimulation in animals and humans. There is evidence for autonomic nervous system dysfunction in SCD, with enhanced sympathetically mediated vasoconstriction reflexes (218, 231–234), which theoretically, could compound any effect of reduced NO. Although there are no data comparing CVR, CA, and the interaction between them in SCD, a vulnerability in the availability of regulatory agents, either alone or in combination with autonomic nervous system dysfunction, may mean that normal CVR and CA ranges are right-shifted and/or narrower with loss of the plateau.…”