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Research Papers

Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure

[+] Author and Article Information
David A. Schreier, Omid Forouzan

Department of Biomedical Engineering,
University of Wisconsin,
2146 ECB, 1550 Engineering Drive,
Madison, WI 53706

Timothy A. Hacker, John Sheehan

Department of Medicine,
1685 Highland Avenue,
5158 Medical Foundation Centennial Building,
Madison, WI 53705-2281

Naomi Chesler

Department of Biomedical Engineering,
University of Wisconsin,
2146 ECB, 1550 Engineering Drive,
Madison, WI 53706;
Department of Medicine,
1685 Highland Avenue,
5158 Medical Foundation Centennial Building,
Madison, WI 53705-2281
e-mail: chesler@engr.wisc.edu

1Corresponding author.

Manuscript received August 3, 2015; final manuscript received November 30, 2015; published online January 27, 2016. Editor: Victor H. Barocas.

J Biomech Eng 138(2), 021012 (Jan 27, 2016) (7 pages) Paper No: BIO-15-1387; doi: 10.1115/1.4032187 History: Received August 03, 2015; Revised November 30, 2015

Patients with sickle cell anemia (SCD) and pulmonary hypertension (PH) have a significantly increased risk of sudden death compared to patients with SCD alone. Sickled red blood cells (RBCs) are stiffer, more dense, more frequently undergo hemolysis, and have a sixfold shorter lifespan compared to normal RBCs. Here, we sought to investigate the impact of increased RBC stiffness, independent of other SCD-related biological and mechanical RBC abnormalities, on the hemodynamic changes that ultimately cause PH and increase mortality in SCD. To do so, pulmonary vascular impedance (PVZ) measures were recorded in control C57BL6 mice before and after ∼50 μl of blood (Hct = 45%) was extracted and replaced with an equal volume of blood containing either untreated RBCs or RBCs chemically stiffened with glutaraldehyde (Hct = 45%). Chemically stiffened RBCs increased mean pulmonary artery pressure (mPAP) (13.5 ± 0.6 mmHg at baseline to 23.2 ± 0.7 mmHg after the third injection), pulmonary vascular resistance (PVR) (1.23 ± 0.11 mmHg*min/ml at baseline to 2.24 ± 0.14 mmHg*min/ml after the third injection), and wave reflections (0.31 ± 0.02 at baseline to 0.43 ± 0.03 after the third injection). Chemically stiffened RBCs also decreased cardiac output, but did not change hematocrit, blood viscosity, pulmonary arterial compliance, or heart rate. The main finding of this study is that increased RBC stiffness alone affects pulmonary pulsatile hemodynamics, which suggests that RBC stiffness plays an important role in the development of PH in patients with SCD.

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Figures

Grahic Jump Location
Fig. 1

Normalized mPAP for (a) blood replacement with chemically stiffened RBCs and (b) blood replacement with control RBCs. *P < 0.05 versus CTL; †P < 0.05 versus first blood replacement.

Grahic Jump Location
Fig. 2

Normalized CO for (a) blood replacement with chemically stiffened RBCs and (b) blood replacement with control RBCs. *P < 0.05 versus CTL; †P < 0.05 versus first blood replacement.

Grahic Jump Location
Fig. 3

Normalized PVR (Z0) calculated as mPAP/CO for (a) blood replacement with chemically stiffened RBCs and (b) blood replacement with control RBCs. *P < 0.05 versus CTL; †P < 0.05 versus first blood replacement.

Grahic Jump Location
Fig. 4

Normalized pulmonary arterial wave reflections (RQ) calculated as the ratio of the amplitude of backward traveling components (Pb) to forward traveling components (Pf) for (a) blood replacement with chemically stiffened RBCs and (b) blood replacement with control RBCs. *P < 0.05 versus CTL; †P < 0.05 versus first blood replacement.

Grahic Jump Location
Fig. 5

Normalized characteristic impedance (ZC) calculated from dP/dQ when flow reaches 95% of its maximal value for (a) blood replacement with chemically stiffened RBCs and (b) blood replacement with control RBCs. *P < 0.05 versus CTL; †P < 0.05 versus first blood replacement.

Grahic Jump Location
Fig. 6

Shear stress versus shear rate for donor whole blood(donor) and whole blood from mice after three blood replacements with chemically stiffened RBCs (Stiff RBC replacement) obtained using an oscillatory tube viscometer. *P < 0.05 versus CTL.

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