Blood Rheology and Hemodynamics: Still Illuminating after 20 Years^[*]

Interactions between the fluidity of blood and the function of the cardiovascular system are complex and intensely studied, and yet remain poorly understood beyond niche clusters of experts. In health, cardiovascular hemodynamics and the rheology of blood are critical to optimal performance and survival alike, and when perturbed underpin many pathologies. Indeed, various congenital and acquired heart diseases, and hematological disorders represent hallmarks of suboptimal hemodynamics and/or blood rheology, although clinical attention and therapeutics are typically narrowband. The seminal review published in the October 2003 issue of Seminars in Thrombosis and Hemostasis[1] presents an integration of topics that include fundamental rheology concepts, cardiovascular hemodynamics, and the intersection of the two.

In this integration, there were four key concepts: (1.) Rheology as the scientific study of the deformation and flow of materials, including solids, liquids, and gases; (2.) Hemorheology as the scientific study of the “flow and deformation behavior of blood and its formed elements”; (3.) Clinical aspects and effectors of hemorheology; (4.) The role of rheology in hemodynamics. Scientifically, the original paper weaved meaning through centuries of research in cardiovascular and blood research and intended to shed light into processes “beyond the textbook,” which have shaped major research themes in the intervening time. Educationally, this work remains “required reading” in many field-leading laboratories when onboarding new staff and/or forming new interdisciplinary collaborations. The lasting impact of this review is evidenced in the number of citations this work has received and the impact on diverse disciplines spanning medicine (e.g., hematology, internal medicine, vascular disease), basic science (e.g., molecular biology, biophysics, physical chemistry), and applied fields (e.g., pharmacology, instrumentation, biomedical engineering). It was always the goal of the original publication to make contributions that remain instructive to investigators 20 years following publication and create touchstones for future generations to return for guidance.

A couple of “long-range” ideas posited remain relevant: (1) the effects of any hemorheological abnormality on organ/tissue blood flow will depend on the amount of “vascular reserve” available, if vasodilation is adequate then only minimal changes occur in overall blood flow, and (2) red blood cell (RBC) distribution can be markedly affected by RBC rheological changes (deformability, aggregation), yet overall flow minimally affected. These topics challenge future cardiovascular and hemorheology researchers to accurately assess rheology in the context of disease while wrestling with the fact that in a healthy vascular system, changes in blood rheology will be compensated by converse changes in the endothelium to preserve resistance to blood flow.

Shear-dependent whole blood viscosity, is a determinant of vascular resistance, which can be described by the fluid dynamic version of Ohm's Law ([Equation 1]).

Eq. 1.

∆P = change in pressure across a vascula bed, Q = flow, R = resistance

Clinically, blood pressure is the dependent variable, set by the cardiac output and resistance. Poiseuille expanded on this equation, better defining resistance as the separate contributions of blood mechanics and vessel geometry ([Equation 2]).

Eq. 2.

μ = shear - dependent blood viscosity, L = vessel length, R = vessel radius

At the time of the original publication,[1] RBC were thought to be a passive player in the equation defining resistance to blood flow, as these cells have no nucleus or organelles. This work highlighted fundamental mechanical interactions between blood flow and the endothelium whereby vascular reserve dictates the impact of rheologic changes. If there is adequate vascular reserve, alterations in blood viscosity would alter wall shear stress causing reflex dilatory or constrictor response. However, in the decades since this seminal work was published, refreshed interest in blood rheology has been sparked owing largely to a paradigm shift indicating the presence of active mechanosensitive and biochemical pathways within RBC. Indeed, while Bor-Kucukatay et al demonstrated convincingly that nitric oxide donors modulated cellular deformability in RBC,[2] extending prior suggestions that these cells could synthesize their own nitric oxide, the presence of nitric oxide synthase was not definitively identified in RBC until 2006.[3] Hypoxic vasodilation in the microcirculation is dependent on the RBC and while the mechanism is still controversial, it is mediated in part by biochemical pathways within the RBC.[4] [5] [6] Further, increased attention on mechanosensitive pathways in RBC emerged after the seminal work of the Patapoutian laboratory describing the PiezoX family of mechanically activated cation channels[7]; Piezo1 in red cells is of particular interest given the unique mechanical properties of these cells among all mammalian cell lines, and has been shown to explain rare hematological disorders[8] while also being the primal event in local nitric oxide generation.[9] Red cells were only recently shown to be one of the primary reservoirs of microRNA[10]—despite being devoid of translational machinery—and may possibly transfer this material via mechanical processes. Thus, study of blood rheology in the molecular era has renewed vigor given the “modern” and holistic view of RBC being profoundly more complex than the conventional view that these cells are little more than an oxygen transporter.

Several fields including general medicine and medical engineering are actively pursuing the interactions between blood rheology and hemodynamics. Sickle cell anemia, for example, is the quintessential intersection of rheologic and vascular disease[11] because the fundamental defect in sickle cell anemia is decreased RBC deformability due to hemoglobin polymerization.[12] [13] Hemoglobin S polymerization also leads to cellular oxidative stress,[14] damaged RBC membrane, cell fragility, and hemolysis.[15] [16] Through its hemolytic release of intracellular hemoglobin and arginase, bioavailability of nitric oxide in the vascular system is decreased leading to a diffuse vasculopathy. Increased red cell adhesion proteins expressed on the cell membrane result in microvascular occlusion in the capillaries and postcapillary venules,[17] and pruning of the microcirculation. In combination with pruned microvascular cross-sectional area, the presence of increased microcirculatory blood flow due to anemia, compounds the stress and damage in the microcirculation. The vascular pathophysiology of sickle cell anemia highlights the complex interaction of abnormal blood rheology and vascular damage that is in part mechanical, cellular, and biochemical abnormality.

Similar multisystem organ dysfunction is the hallmark complication of advanced heart failure and particularly among those receiving mechanical circulatory support (MCS) such as implantable ventricular assist devices and/or extracorporeal membrane oxygenation. Although the current generation of MCS are lifesaving technologies, the associated mechanical stress and exposure to artificial materials result in profound changes to the plasma membrane of the RBC leading to increased fragility and hemolysis. Despite the shear stresses within MCS now being below the hemolytic threshold, Baskurt and Meiselman's contributions demonstrated that this so-called threshold is not fixed, but rather may be manipulated by the duration and magnitude of shear stress.[18] In addition to adverse cardiovascular effects from hemolysis, it appears that supraphysiological shear stress alters the surface chemistry and membrane composition of the cell, thus leading to increased cellular aggregation[19] and decreased deformability,[20] [21] respectively; such changes are predicted to alter blood–endothelial interactions and microcirculatory flux without change to bulk flow/pressure.[22] The original paper[1] posited that “subclinical” changes in blood rheology impact vascular function and microcirculatory oxygen supply demand matching in multiple disease states, but are difficult to prove in short-term studies. The possibility that chronically elevated, albeit subhemolytic, shear stresses may present a primary contributor to seemingly unrelated multiorgan dysfunction is being evaluated in the context of MCS and elsewhere.

A final example at the forefront of recent rheological developments is made in a unique circulation that has only existed for the past 50 years due to the advent of the Fontan surgery used to treat rare congenital heart disease.[23] This surgery results in ultralow shear and nonpulsatile blood flow in the pulmonary arterial system, which is typically high shear and pulsatile. In a normal biventricular circulation, RBC aggregates (rouleaux) that are normally present in the systemic venous circulation are disaggregated in the right atrium, right ventricle, and pulmonary artery. Vortexing in the atrium and ventricle as well as high shear-rate flow in the pulmonary artery monodisperse RBC for distribution in the microcirculation, decrease viscosity due to the shear-thinning nature of blood and allows for even distribution of RBC in the microcirculation. In the Fontan circulation, low shear blood flow and rouleaux persist in the pulmonary arterial circulation, increasing resistance and potentially causing maldistribution of RBC in the pulmonary microcirculation. It was recently discovered that these patients naturally decrease RBC aggregation and therefore lower shear viscosity at equivalent hematocrits compared with healthy controls. In this unique circulation lower blood viscosity is associated with increased pulmonary blood flow.[24] [25] Univentricular physiology after the Fontan palliation presents a new avenue to understand the role of non-Newtonian fluid mechanics of blood in the cardiovascular system.

The educational vision outlined at the closure of the 2003 paper[1] remains a challenge for basic science and clinical approaches. It stands that in the context of a functional endothelium, any impairment in rheological properties of blood may be compensated through vasoregulatory processes. Further, the “chicken-and-egg” dilemma has not yet been resolved for many rheological disorders, given factors that impact cellular properties (e.g., oxidative stress) exert impairments to global tissues. Thus 20 years on, it remains that the complexities of physiological redundancy and the interdependence of blood flow and vascular health presents an entanglement that will only be addressed through interdisciplinary approaches. Further, emergent methods of observation employing tissue-specific genetic manipulation of blood properties in the absence of vascular impairment and vice versa present opportunities to better understand this problem. It is the goal of this editorial to highlight progress in the field, to present remaining challenges, and to continue to educate and inspire future generations of blood and cardiovascular researchers.

^* Dedicated to the memory of Oguz Baskurt. Dr. Baskurt was a Professor of Physiology at Koc University, Istanbul, Türkiye, and died unexpectedly in 2013. He was a cherished collaborator and mentor. With Dr. Meiselman, they carried out several cooperative research projects and coauthored over 60 peer-review publications.

Publication History

Article published online:
30 April 2024

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