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

Frontiers in Physiology. 2019;10 DOI 10.3389/fphys.2019.00381

 

Journal Homepage

Journal Title: Frontiers in Physiology

ISSN: 1664-042X (Online)

Publisher: Frontiers Media S.A.

LCC Subject Category: Science: Physiology

Country of publisher: Switzerland

Language of fulltext: English

Full-text formats available: PDF, HTML, ePUB, XML

 

AUTHORS


Patjanaporn Chalacheva (Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States)

Roberta M. Kato (Divisions of Pulmonology, Children’s Hospital Los Angeles, Los Angeles, CA, United States)

Payal Shah (Hematology Section, Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States)

Saranya Veluswamy (Hematology Section, Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States)

Christopher C. Denton (Hematology Section, Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States)

John Sunwoo (Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States)

Wanwara Thuptimdang (Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States)

John C. Wood (Divisions of Cardiology, Children’s Hospital Los Angeles, Los Angeles, CA, United States)

Jon A. Detterich (Divisions of Cardiology, Children’s Hospital Los Angeles, Los Angeles, CA, United States)

Thomas D. Coates (Hematology Section, Children’s Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States)

Michael C. K. Khoo (Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 14 weeks

 

Abstract | Full Text

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.