The “coronary slow flow phenomenon” is the angiographic finding of delayed flow from the epicardial coronaries to the microvasculature in the absence of an anatomic obstruction and is found in roughly 1% of diagnostic angiograms.1 Because of sluggish perfusion and attendant ischemia, patients may present with unstable angina, ECG abnormalities, potentially fatal arrhythmias, or myocardial infarction.
Conditions associated with coronary slow flow include smoking, hyperuricemia, hyperhomocystinemia, hyperlipidemia, increased body mass index, and the metabolic syndrome.1-3 Gori et al., who suggested the term “Syndrome Y” for this phenomenon, characterized patients as most commonly young, male smokers.4 The pathogenesis of the condition is poorly understood, but not surprisingly, the usual suspects, endothelial dysfunction and inflammation, are often invoked.
Coronary Slow Flow As A Rheological Disease
As is the case with hypertension, atherosclerosis, and the metabolic syndrome, coronary slow flow is an established clinical entity whose pathogenesis is obscure when the role of blood viscosity is ignored. The coronary slow flow phenomenon is an example of “rheologic obstruction,” a condition described by Burch and DePasquale in 1965,5 seven years before the coronary slow flow phenomenon was identified. In order to understand rheological obstruction, which can be viewed as a manifestation of flocculation (also known as agglomeration, coagulation, or aggregation, see Figure 1), it may be helpful to review basic principles of colloid chemistry.
Figure 1. Colloids, such as erythrocytes, can flocculate or aggregate if attractive forces between them are greater than repulsive forces. (Diagram by Williams 12357, courtesy of Wikimedia Commons)
A colloid is a substance microscopically dispersed throughout another substance. In blood, erythrocytes are the colloid suspended in plasma. Some colloids are important pharmaceuticals, such total parenteral nutrition mixtures. The shelf life of colloids can be limited by flocculation, which occurs when attractive forces are greater than electrostatic repulsive forces. In colloids, viscosity is also modulated by the balance of attraction and repulsion of the colloidal particles. The viscosity of colloids ranges from that of cement to turbid water.
The zeta potential (Figure 2) is the electrical potential created by a charged particle in a salt solution. The stability or resistance of a colloid to flocculation is determined by the magnitude (positive or negative) of the zeta potential. Colloids with greater zeta potentials are more stable and resistant to flocculation.
Erythrocytes have a negative surface charge due to the presence of sialic acid on their surface. The zeta potential of blood is the difference between the charge of the erythrocyte surface and plasma. The electronegative erythrocyte surface attracts and is surrounded by a layer of counterions, in this case sodium cations. These screen and neutralize the electronegative erythrocyte surface charge. There is a smaller number of anions, called “co-ions,” which are attracted to the cations.
The charge and density of this ion cloud decrease with the distance from the erythrocyte surface until they are similar to those of the bulk phase. The interaction of two screening clouds, which will have a preponderance of positive charges, keep erythrocytes apart, stabilizing the colloid and preventing erythrocyte aggregation or flocculation.
Figure 2. Zeta Potential. In blood, the colloid is the erythrocyte. Its electronegative surface attracts layers of sodium cations, which screen and neutralize the negative surface charge. (Diagram from Mjones 1984, adapted from Larryisgood. Courtesy of Wikimedia Commons)
The ionic strength of plasma, as well as the surface charge of the erythrocyte, determines the zeta potential of blood. Ionic strength is manipulated in blood banking to foster hemagglutination reactions. IgG immunoglobulins are too small (diameter 12 nm) to simultaneously bind two erythrocytes, which are separated by a distance of 18 nm.6 However, if erythrocytes are suspended in “LISS” or low ionic strength saline, then the erythrocyte zeta potential is decreased and they can approach each other more closely. IgG can then overcome the zeta potential and simultaneously bind two erythrocytes, causing visible hemagglutination. Uric acid also decreases the zeta potential and augments erythrocyte aggregation (see below).
The zeta potential of blood is -18 mV.6 In a five-tiered scale with flocculation at one end and excellent stability at the other, colloids with a zeta potential between -10 and -30 mV, like blood, are classified as having “incipient instability,” the second to least stable class.7 This increases the chances of flocculation and erythrocyte aggregation and serves as an enabling condition for the coronary slow flow phenomenon.
The association of hyperuricemia with coronary slow flow provides a clue into its pathogenesis and the role of uric acid in atherosclerotic cardiovascular disease. Elevated levels of uric acid affect zeta potential. Uric acid, being larger than sodium ions or chloride (the molecular weight of urate is 168 g/mol vs. 23 g/mol for sodium and 58 g/mol for chloride), are capable of steric shielding and weakening the zeta potential.
Steric shielding occurs when a charge is seemingly weakened or spatially shielded by an oppositely charged molecule. In this case, larger urate molecules block some sodium cations from being attracted to and surrounding the erythrocytes. Thus, erythrocytes will have a smaller screening cloud of ions and will be able to approach each other more closely, increasing the chances for flocculation or aggregation (Figure 3).
Figure 3. Erythrocytes with IgG on their surface were incubated with uric acid (right panel). Without uric acid (left panel), erythrocytes have little tendency to aggregate. In the panel on the right, the degree of aggregation approaches flocculation (magnification 100x). Thanks to Melissa Wagnild for her technical assistance with these experiments.
I characterize hyperuricemia as a weak risk factor for cardiovascular disease,8 significant in some studies but not others. I argue that indirect effects on cardiovascular disease, such as by modulations of zeta potential, erythrocyte aggregation, and low shear blood viscosity, are consistent with the impact of a weak risk factor. In distinction, a strong risk factor such as hypertension, for example, increases arterial stiffness and is associated with increased blood viscosity across a wide range of shear.
Flocculation or aggregation should occur in any vascular bed with insufficient shear or flow to break up the reversible aggregates. Why is slow flow most closely associated with the coronary circulation? Burch and DePasquale noted that isometric contraction of the left ventricle is associated with a sudden decrease in left but not right coronary artery flow.5 This abrupt decrease in shear results is a marked increase in viscosity due to erythrocyte aggregation in this vessel. As Burch and DePasquale wrote, “Obviously, the greater the rise in viscosity, the more energy is required to reinstitute forward flow during the ejection phase of systole,” which illustrates the concept of rheologic obstruction. Indeed, the left anterior descending artery has the slowest flow compared to the circumflex and right coronaries in case reports of the slow coronary flow phenomenon.
Augmented erythrocyte aggregation and increased blood viscosity explains the site-specificity of the majority of myocardial infarctions (60 to 70 percent) in the distribution of the left coronary artery. Another reason for the apparent predominance of slow flow in the coronary circulation may be that the myocardium is a net exporter of urates in vivo.12 However, cerebral blood flow has been noted to be slower in patients with slow coronary flow phenomenon. Thus, the slow flow phenomenon is not restricted to the coronary circulation.
Why Didn’t Evolution Make Blood A More Stable Solution?
I argue that erythrocyte aggregation occurs in the microvasculature causing the coronary slow flow phenomenon and that blood has “incipient instability” regarding its tendency to flocculate. A natural counterargument is as follows: If erythrocyte aggregation is an incipient hazard, humans would have evolved a greater zeta potential and more flocculent-proof blood. This could be accomplished either by increasing the ionic strength of plasma or increasing the electronegative surface charge of erythrocytes.
However, a more stable colloidal solution would interfere with two vital processes, inflammation and hemostasis. In the inflammatory response, the hematocrit in post-capillary venules approaches 100% as plasma leaves the circulation and erythrocytes become maximally compacted. This causes stasis of blood in the upstream capillaries, allowing neutrophils to adhere to the endothelium, marginate, and exit the circulation to participate in inflammation. Erythrocytes would not be able to form such a compact mass if their zeta potential were greater because this would result in a thicker screen of cations and plasma preventing a solid mass from forming. (Figure 5).
Figure 5. In the venule on left, the hematocrit is beginning to increase as plasma leaves the intravascular space. In the vessel on the right, the erythrocytes are maximally compacted, and the hematocrit approaches 100%.
Erythrocytes must also form a solid mass when a blood clot contracts, opposing the edges of the wound. Greater zeta potential would, therefore, prevent normal blood coagulation and the formation of a solid mass (Figure 6).
Figure 6. Fresh blood clot on the left; same clot 48 hours later on the right. The clot has retracted from the test tube wall, leaving a surrounding layer of yellow serum.
1. Diverse Spectrum of Presentation of Coronary Slow Flow Phenomenon: A Concise Review of the Literature. Chaudhry MA, Smith M, Hanna EB, Lazzara R. Cardiology Research and Practice 2012; 383181. http://dx.doi.org/10.1155/2012/383181
7. Zeta potential. http://en.wikipedia.org/wiki/Zeta_potential
14. Yayali YT, Susam O, Demir E. Increased red blood cell deformability and decreased aggregation as potential adaptive mechanisms in the slow coronary flow phenomenon. Coronary Artery Disease 2013; 24: 11-15.
For Further Reading:
1. The Fall and Rise of Kilmer McCully, NY Times, August 10, 1997.
2. Pharmaceutical Formulations and The Importance of Zeta Potential to Pharmaceutical Formulations With Supplier Data by Malvern http://www.azonano.com/article.aspx?ArticleID=1234#_Zeta_Potential_and_1
3. Depletion force. http://en.wikipedia.org/wiki/Depletion_force
4. Colloid. http://en.wikipedia.org/wiki/Colloid
5. Flocculation. http://en.wikipedia.org/wiki/Flocculation
6. Steric effects. http://en.wikipedia.org/wiki/Steric_shielding
7. Zeta potential. A complete course in 5 minutes. http://www.zeta-meter.com/5min.pdf
8. Particle aggregation. http://en.wikipedia.org/wiki/Particle_aggregation
Last Updated: 2014-12-30