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Vascular Stenosis

Hemodynamics and Drug Elution

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PanVascular Medicine

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Abstract

An arterial stenosis is a narrowing of the lumen that disturbs the local blood flow and precludes the adequate irrigation of perfused organs. A vascular stenosis can be extrinsic, which is caused by external compression (e.g., aneurysms and tumors), or intrinsic, currently related to atherosclerosis.

Atherosclerosis is defined by an intramural retention of lipids coupled to inflammation and dyslipidemia. Atherosclerosis scatters throughout large and medium thick-walled systemic arteries, especially near and in branching regions. (Pulmonary arterial stenosis is a congenital defect.)

Atherosclerosis is characterized by migration from the media, proliferation, and dedifferentiation of vascular smooth myocytes in the subendothelial layer, in addition to monocyte diapedesis and differentiation into macrophages. Both smooth myocytes and macrophages scavenge accumulated oxidized low-density lipoproteins (oxLDL) and transform into foam cells. Atherosclerosis produces symptoms when the arterial lumen is severely narrowed.

Advanced atherosclerotic plaques can be destabilized, thereby being a source of clotting and subsequent emboli. Emboli block tissue perfusion in a smaller downstream artery, thereby causing ischemia and infarction.

The treatment of stenotic arterial segments relies on surgical grafting or medical minimally invasive procedures such as stenting. However, both methods often lead to intimal hyperplasia resulting from uncontrolled proliferation of vascular smooth myocytes. Whereas atheroma evolves during a time magnitude order of 10 years, posttherapeutic intimal hyperplasia develops in a period of order 1 month.

Successful stenting can be assumed as a procedure without strong endothelial injury. In other words, both delayed thrombosis and intimal hyperplasia result from stent deployment that more or less severely damages the vascular endothelium. To eliminate these complications, drug-eluting stents have been designed and fabricated. However, the antiproliferative drug not only blocks vascular smooth myocyte division but also precludes endothelium healing. In the absence of proper endothelial interface between blood and arterial wall, that is, when the local controller of blood coagulation and cell proliferation is missing, thrombosis and restenosis occur.

Arterial stenoses have stimulated biomechanicians and applied mathematicians. They carried out flow visualization and pressure and velocity measurements in experimental models of stenoses with idealized, symmetrical or not, geometry. In parallel to technological improvements of medical imaging techniques, computational fluid dynamics, due to new numerical schemes and high-performance computing, enables to perform numerical tests on subject-specific compartments of the blood circulation, after 3D reconstruction, rather than focusing on more or less short arterial, branched or not, segments. In addition, the drug release from drug-eluting stents is investigated using mathematical models.

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Notes

  1. 1.

    A pressure difference refers to measurements over a macroscopic length, that is, at two stations separated by a finite distance. A pressure gradient denotes a pressure change over an infinitesimal length, that is, in a tiny control volume.

  2. 2.

    Arginase-l (Argl) is the enzyme that converts arginine to ornithine. Resistin-like-α (RetnLα) is also called found in inflammatory zone 1 (FIZZ1) protein. Expression of both FIZZ1 and FIZZ2 (RetnLβ), but not FIZZ3 (resistin [Retn]), is upregulated after antigen challenge in an STAT6-dependent fashion (Stütz et al. 2003). Factor STAT6 directly regulates IL4- and IL13-triggered induction of FIZZ1 production by cooperating with CCAAT/enhancer-binding protein (C/EBP).

  3. 3.

    Plasma concentration of elastokine ranges from ng/ml to μg/ml values depending on both the dosage procedure and the atherosclerosis evolution degree (Gayral et al. 2014).

  4. 4.

    Two other elastokine receptors include αvβ3-integrin and galectin-3. They do not have any associated sialidase activity.

  5. 5.

    Sialidases remove terminal sialic acid from glycolipids and glycoproteins. In human monocytes, subtypes lysosomal Neul, plasma membrane-tethered Neu3, and Neu4 can be detected (but not Neu2). Sialidase activity of monocytes increases up to 14-fold, but that of cathepsin-A, β-galactosidase, and alkaline phosphatase rises only two to three times during differentiation of monocytes into macrophage (Stamatos et al. 2005). The amount of Neul and Neu3 elevates, whereas that of Neu4 decays.

  6. 6.

    Stenoses from 30 % to 80 % reduction gradually lower the early systolic peak and only slightly affect the mid-systolic peak or mean flow (Schoenberg et al. 2000).

  7. 7.

    Either R(z)/R = 1 − h s /2R(1 + cos(πz/(L s /2)))) where h s is the stenosis throat thickness and L s the stenosis length (Deshpande and Giddens 1980; Siegel et al. 1994), or R(z)/R = 1 − exp{−(2z/R)2}/2 (Deplano and Siouffi 1999).

  8. 8.

    The pulsatile flow is a nonzero mean sinusoidal flow with mean Reynolds number \( \overline{\mathrm{Re}}=575 \) and unsteady component amplitude Re~ = 360 and Stokes number Sto = 7.5.

  9. 9.

    Flow was assumed laminar and blood Newtonian and incompressible. The rheology of the normal and diseased arterial segments is modeled by a hyperelastic, isotropic, incompressible, and homogeneous material that obeys a Mooney–Rivlin behavior. An anisotropic (transversely isotropic) strain energy density function is obtained by adding an anisotropic term to the Mooney–Rivlin strain energy function.

  10. 10.

    Concentration of LDL particles must be less than 1 g/l. More than 1.3 g/l, especially associated with at least two risk factors for cardiovascular disease, requires treatment.

  11. 11.

    The earliest detectable event in atherogenesis is the accumulation of oxidized lipoproteins in focal areas of the arterial subendothelium. Lipoprotein aggregation and proteoglycan binding to the extracellular matrix increase particle size and thus impede egress from the arterial wall. The lipoproteins retained in the extracellular matrix trigger inflammation.

  12. 12.

    Most forms of oxidized LDLs do not strongly transform cultured macrophages into foam cells. Lipoproteins in focal areas of the arterial subendothelium. Lipoprotein aggregation and proteoglycan binding to the extracellular matrix increase particle size.

  13. 13.

    Remnant lipoproteins activate ACAT and modify cultured macrophages into foam cells.

  14. 14.

    Proprotein convertases process latent precursor proteins into active products, Ca2+-dependent serine peptidases. Their targets include proparathyroid hormone, transforming growth factor-β1 precursor, proalbumin, proβ-secretase, membrane type-1 matrix metallopeptidase, β-subunit of pronerve growth factor, and von Willebrand factor. Subtilisin was initially obtained from Bacillus subtilis. Subtilases (>200 known species) are subtilisin-like serine peptidases. Kexin is a prohormone processing peptidase in the budding yeast (Saccharomyces cerevisiae), which shares structural similarities with the bacterial peptidase subtilisin. The first identified mammalian homologue was furin (FUR: FeS upstream region), which belongs to the subtilisin-like proprotein convertase category. Furin-like proprotein convertases process hemojuvelin.

  15. 15.

    Chemokines CCL5, CXCL1, and CXCL8 are involved in arrest of rolling leukocytes on the wetted surface of the endothelium of atherosclerotic arteries.

  16. 16.

    Thyroid hormones affect growth, metabolism, and activity of nearly all organs by activating their nuclear receptors. Four thyroid hormone receptors exist (THRαl–THRαl2 [nuclear receptors NRlal-l–NRlal-2] and THRβi–THRβ2 [NRla2-l–NRla2-2]) with a differential expression among body tissues. Subtype THRβ is predominant in the liver. It is responsible for cholesterol decay. Subtype TRα is the major type in the heart. It generates most of the cardiovascular effects.

  17. 17.

    Glycolaldehyde is an advanced glycation end product.

  18. 18.

    Platelets abundantly express ScaRb3 that connects to thrombospondin-1 and oxidized low-density lipoproteins. Both ligand types limit the activation of platelets in suspension (Nergiz-Unal et al. 2011). However, immobilized TSpl and oxLDL, but not LDL, strongly support platelet adhesion and spreading via a SYK kinase- dependent Ca2+ signaling.

  19. 19.

    Binding of ScaRb3 to thrombospondin-1 hampers VEGF signaling from VEGFR2, hence angiogenesis. Upon thrombospondin action, ScaRb3 enables linkage of ΡΤΡηβ phosphatase with VEGFR2 in microvascular endotheliocytes (Chu and Silverstein 2012). Phosphorylation of ScaRb3 by protein kinase-Ca on its extracellular domain prevents its binding to thrombospondin-1 as well as represses ligand-mediated recruitment to ScaRb3 of SRC family kinases.

  20. 20.

    Calcium influx, which triggers the contraction of smooth myocytes, mainly occurs through voltage-gated Cay 1.2 channels.

  21. 21.

    A.k.a. protein kinase-like endoplasmic reticulum kinase (PERK).

  22. 22.

    A.k.a. inositol-requiring protein IRe1 (or IRe1a).

  23. 23.

    Macrocalcifications have size greater than 100 μm.

  24. 24.

    Solid cavitation is a physical process that differs from cavitation in fluids. In fluids, small bubbles grow when their vapor pressure exceeds the local pressure of the surrounding fluid.

  25. 25.

    CD133+ progenitor cells can differentiate into mastocytes. They produce adhesion molecules and receptors involved in transmigration as well as tryptase. The latter activates peptidase-activated receptor PAR2 on endotheliocytes and increases calcium-independent phospholipase-A2 activity in human coronary artery endotheliocytes. Plasma levels of lipoprotein-associated PLA2, a biomarker for vascular inflammation, are correlated to CD133+ cells.

  26. 26.

    Production of 2-arachidonoylglycerol is enhanced by PAF receptor-mediated phospholipase activation with a fall in hydrolysis due to degradation of fatty acid amide hydrolase. The latter process together with augmented synthesis by activated protein tyrosine phosphatase PTPN is responsible for heightened anandamide concentration.

  27. 27.

    A.k.a. platelet-activating factor acetylhydrolase (PAFAH). It associates with apoB-containing lipoproteins, primarily with LDLs in humans. It hydrolyzes oxidized phospholipids in oxLDL, thereby generating two active lipid mediators, lysophosphatidylcholine (lysoPC) and oxidized non-esterified fatty acids (oxNEFA). Both product types recruit leukocytes; they are cytotoxic to macrophages. Lysohosphatidylcholine can heighten expression of adhesion molecules (e.g., VCAM1) in endotheliocytes and that of chemokines (e.g., CCL2) and cytokines (e.g., IL1ß) in smooth myocytes and monocytes.

  28. 28.

    Enzymes of the phospholipase-A2 superfamily hydrolyze fatty acids at the sn2 position of glycophospholipids.

  29. 29.

    Dendritic cells are antigen-presenting cells that participate in initiation of adaptive immune response. Blood-derived monocytes can differentiate into mature dendritic cells. The monocyte surface marker lipopolysaccharide receptor (LPSR, or CD14) is downregulated, whereas dendritic cell surface markers TN- FRSF5, ICAM1, L-selectin, β3-integrin, and CD83, as well as viral and bacterial capture and uptake lectin dendritic cell-specific ICAM3-grabbing nonintegrin (DCSIGN) and costimulator TNFRSF5, are upregulated. However, g2aPLA2 does not influence expression of CDla and αM-, αX-, β2-integrin chains. Dendritic cells can accumulate in developing atheromatous plaques.

  30. 30.

    In experimental myocardial infarction, the plasma membrane of cardiomyocytes loses its asymmetry because of exposure of the anionic phospholipids phosphatidylserine and phosphatidylethanolamine to the outer membrane leaflet.

  31. 31.

    The amount of tissue damage after an infarction determines the morbidity.

  32. 32.

    Water permeability is associated with an index defined by water flow rate through a given area of sample graft under a given pressure.

  33. 33.

    The usable length is the length under a prescribed load.

  34. 34.

    Percutaneous coronary intervention is associated with an antithrombotic, anti-inflammatory, and antioxidant therapy, as well as other drugs, such as antagonists of calcium channels, inhibitors of sodium–hydrogen exchangers, inhibitors of mitochondrial permeability transition pore, and activators (erythropoietin, statins, natriuretic peptides, glucagon-like peptide-1, and morphine) of prosurvival protein kinases of the reperfusion injury salvage kinase pathway (ischemic postconditioning) (Hausenloy and Yellon 2008 ).

  35. 35.

    Mechanical tests determine, in particular, expanded diameter for a selected pressure range (0 ≤ p ≤ 800 kPa), recoil, radial stiffness (pressure exerted by the vessel wall at which the intravascular device do not resist), fatigue, crimp (stent–balloon adherence), bending stiffness, and shortening due to expansion.

  36. 36.

    Early, late, and very late in-stent thromboses occur in the first 30 days, between 1 month and 1 year and beyond 1 year after stent implantation, respectively. Probable and possible stent thromboses correspond to myocardial infarction or unexplained death within 30 days and beyond 30 days after stent implantation, respectively. Used in initial treatment, drug-eluting stents with respect to bare-metal stents are associated with lower revascularization rates and higher risk of late stent thrombosis, but there is no difference in mortality up to 4 years in patients initially treated with either sirolimus-eluting, paclitaxel-eluting, and bare-metal stents (Daemen et al. 2009) Yet, sirolimus-eluting stents have 15–20 % lower risk for myocardial infarction than the other two. The ENDEAVOR program that evaluates zotarolimus-eluting stent shows significantly lower cardiac death and myocardial infarction MI rates than those of bare-metal stents up to 3 years.

  37. 37.

    Tested strut numbers are equal to 24, 48, 96, 192, 384, and ∞.

Abbreviations

Arteriosclerosis vascular disease:

Arteriosclerosis vascular disease characterized by stiffer and thicker arterial walls, among which those occurring during aging. Among these diseases, atherosclerosis is defined by an intramural retention of lipids coupled to inflammation and dyslipidemia. In fact, arteriosclerosis and atherosclerosis that have been termed by Lobstein in 1848 and by Marchand in 1903, respectively, designate different aspects of the same disease.

Atheroma central core of an atherosclerotic plaque:

It is characterized by the accumulation of necrotic cells and debris, lipids, as well as calcium. It is practically devoid of living cells. It is bordered by a rim of lipid-laden macrophages surrounded by a variable amount of fibrous connective tissue. This pathological soft tissue is highly thrombogenic.

Atherosclerosis vascular disease:

Atherosclerosis vascular disease characterized by an endothelial dysfunction, intimal accumulation of oxidized lipoproteins and migrating cells that transform into foam cells, and inflammation.

ATP-Binding Cassette (ABC):

ATP-binding cassette (ABC) transporter plasmalemmal protein coupled to ATP hydrolysis that carries various substrates across cellular membrane, such as metabolites, lipids and sterols, and drugs. In particular, it regulates efflux of lipids. Four members of the ABC superclass control the delivery and disposal of cholesterol. Whereas ABCg5 and ABCg8 impede intestinal absorption of dietary sterols and promote hepatobiliary secretion of sterols, ABCal and ABCgl involved in the reverse cholesterol transport pathway elicit cholesterol egress from cells.

Chemokine:

Chemokine member of a class of cytokines that are chemoattractants, especially causing a directed chemotaxis of leukocytes to sites of inflammation and infection according to a concentration gradient, once they have excited their cognate receptors on the target cell surface.

Ectopic calcification:

Ectopic calcification pathological deposition of calcium salts and crystallization of hydroxyapatite in the extracellular matrix. Calcium apatite refers to a group of phosphate minerals. These abnormal calcium deposits have diverse crystalline compositions. Calcium phosphate in arteries predominantly deposits on elastin rather than collagen, like in bones.

Endarterectomy:

Endarterectomy surgical procedure used to reduce the risk of infarction by removing an atheromatous plaque that very severely narrows the arterial lumen.

Endocannabinoids:

Endocannabinoids endogenous cannabis-like substances that activate the cannabinoid G-protein-coupled receptors of the active component of Cannabis sativa. The main endocannabinoids derive from arachidonic acid. They serve as cellular lipid messengers. In the brain, they contribute to the regulation of motor control, cognition, emotional responses, motivated behavior, and homeostasis. They serve as retrograde signaling messengers in GABAergic and glutamatergic synapses as well as modulators of postsynaptic transmission. Outside the brain, the endocannabinoid system modulates the activity of the autonomic nervous and immune systems as well as microcirculation. Endocannabinoids are carried into cells by a specific transporter and degraded by two enzymes. Endocannabinoids can lower proliferation of lymphoid cells and their secretion of interferon-γ as well as macrophage infiltration into atherosclerotic plaques. In macrophages, the endocannabinoid axis activated by oxidized low-density lipoproteins promotes intracellular accumulation of cholesterol.

Fatty streak:

Fatty streak histopathological structure that results from the recruitment of monocytes from blood (arterial lumen and parietal neovessels), their differentiation into macrophages, their uptake of lipid particles, and their transformation into foam cells, as well as migration of medial smooth myocytes that also transformed into foam cells. Foam cells, monocytes, T lymphocytes, and smooth myocytes agglomerate and proliferate within the intima. Among these cells, smooth myocytes secrete large amounts of extracellular matrix constituents.

Fibrous cap:

Fibrous cap cholesterol-rich plaque beneath the endothelium formed by the smooth myocyte-derived scar tissue. The fibrous cap encapsulates a necrotic core containing extracellular lipids and cellular debris. It provides the structural integrity of the plaque.

Foam cell:

Foam cell transformed smooth myocyte or macrophage saturated by lipid droplets after unlimited phagocytosis of oxidized LDLs through specific scavenger receptors. Foam cell death, together with extracellular binding of lipids to collagen fibers and proteoglycans, creates the atheroma.

Grafting surgical procedure:

Grafting surgical procedure consisting of vessel replacements and bypasses (bypass grafting). Replacement or end-to-end anastomosis refers to a surgical connection with sutures between ends of both host and graft vessels. Other techniques comprise end-to-side and side-to-end anastomoses. Bypass or side-to-side anastomosis provides an alternate route for the bloodstream to irrigate tissues by bypassing the narrowed or blocked arterial segment (e.g., coronary artery bypass grafting [CABG]).

Interleukin glycoprotein:

Interleukin glycoprotein produced by leukocytes for regulating immune responses. These cytokines are particularly synthesized by T lymphocytes, monocytes, macrophages, and endotheliocytes.

Intimal hyperplasia:

Intimal hyperplasia thickening of the intima of the arterial wall caused by a high density of invading medial smooth myocytes having experienced a change in phenotype that enables proliferation and migration. Intimal hyperplasia is caused by endothelial removal or damage after endarterectomy, grafting, particularly when a vein and synthetic vascular graft is used, or stenting.

Matrix metallopeptidases:

Matrix metallopeptidases zinc-dependent enzymes that degrade constituents of the extracellular matrix as well as numerous active molecules. They can cleave plasmalemmal receptors and inactivate chemokines and cytokines. They are secreted by foam cells.

Oxidative stress:

Oxidative stress process arising from an imbalance between the activity of reactive oxygen species and that of detoxifying agents.

Reactive Oxygen Species (ROS):

Reactive oxygen species (ROS) are reactive by-products of the oxygen metabolism. They include radicals (superoxide) and nonradical reactive oxygen derivatives. Some are highly toxic. At low concentrations, reactive oxygen species operate as cellular messengers. At higher concentrations, they damage cell components, such as nucleic acids, proteins, and lipids. An oxidative stress occurs when ROS cannot be eliminated. Antioxidants regulate oxidative reactions. Preventive antioxidant proteins (albumin, transferrin, myoglobin, ferritin, etc.) hamper ROS formation. Scavenger lipid-soluble and water-soluble antioxidants (vitamins C and E, α- and β-carotene, superoxide dismutase, hydrogen peroxide, and glutathione peroxidase) eliminate ROS.

Scavenger receptor:

Scavenger receptor plasmalemmal molecule that detects and takes up normal and abnormal macromolecules. Many types exist that participate in the removal of many foreign substances and wastes, each scavenger receptor being characterized by its affinity for some ligands. In particular, they recognize oxidized and acetylated low-density lipoproteins.

Stent:

Stent usually a mesh metallic tubular support inserted into a stenosed arterial segment to relieve localized luminal constriction.

Thrombus:

Thrombus abnormal blood clot on a dysfunctional or disrupted endothelium that can fill the lumen of a stenosed segment, or, most often, under high shear stress, eject emboli that are conveyed downstream in smaller arteries or arterioles, thereby causing vascular occlusion and tissue ischemia. Episodic fibrous cap ruptures occurring during inflammation stages, stimulated by inflammatory substance release, initiate thrombus formation.

Toll-like receptor plasmalemmal molecule:

Toll-like receptor plasmalemmal molecule that identifies specific components of microorganisms. Once it is activated, it induces inflammation and the development of antigen-specific adaptive immunity.

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Further Readings

  • Ding J, Liu Y, Wang F, Bai F (2012) Impact of competitive flow on hemodynamics in coronary surgery: numerical study of ITA-LAD model. Comput Math Methods Med 2012:356187

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Further Reading

  • Anatomical and pathophysiological characteristics of stenoses and their treatments are detailed in many textbooks, in addition to the above mentioned references. The impaired structure-function of diseased arterial walls in the presence of atherosclerotic plaques can be analyzed form various aspects: molecular biology (e.g., signaling pathways), histology (e.g., plaque composition), anatomy (e.g., lesion distribution and collateral circulation), physiology (e.g., flow resistance and organ perfusion at rest and exercise), fluid dynamics (e.g., pressure drop, vortices, jet, flow separation, wall shear stress, etc.), invasive and noninavsive, qualitative and quantitative imaging (lesion morphology and localization), modeling (assessment of fields of hemodynamic quantities and parietal stresses as well as intramural drug distribution), and therapy (vulnerable plaques)

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A very short list of books mostly dealing with therapy arising from a rather superficial web search includes:

  • Klabunde RE (2012) Cardiovascular physiology concepts. www.cvphysiology.com/index.html. This web site is an abbreviated content of the textbook Cardiovascular physiology concepts writeen by RE Klabunde and published in its second (2011) edition by Lippincott Williams and Wilkins

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  • Moore WS (ed) (2013) Vascular and endovascular surgery: a comprehensive review, 8th edn. Elsevier – Saunders, Philadelphia, This book presents the latest procedures

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  • Kandarpa K (2007) Peripheral vascular interventions. Wolters Kluwer – Lippincott Williams and Wilkins, Philadelphia, This book describes all endovascular interventions and devices currently-used for arterial and venous diseases, addressing patient selection, procedures and postprocedural management

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  • Casserly IP, Sachar R, Yadav JS (2011) Practical peripheral vascular intervention. Lippincott Williams and Wilkins – Wolters Kluwer, Philadelphia, This book gives the state-of-the-art in vascular interventional procedures for all arteries and veins, except coronary vasculature

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  • Tura A (ed) (2003) Vascular grafts: experiment and modelling. WIT Press, Southampton, This book focuses on end-to-end and end-to-side vascular grafts from a biomechanical point of view with both experimental and numerical simulation approaches

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Authors and Affiliations

  1. Laboratoire Jacques-Louis Lions, CNRS UMR 7598, Team INRIA-UPMC-CNRS REO, University Pierre and Marie Curie, Paris, F-75252, Cedex 05, France

    Marc Thiriet

  2. Department of Mathematics and Statistics, University of Montreal, C.P. 6079, Succursale Centre-ville, Montreal, H3C 3J7, QC, Canada

    Michel Delfour

  3. Department of Mechanical Engineering, Polytechnique Montreal, Case postale CP 6128, succ Centre-ville, Montreal, H3C 3A7, QC, Canada

    André Garon

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  1. Marc Thiriet
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Correspondence to Marc Thiriet .

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  1. Akademisches Lehrkrankenhaus MLU, Bitterfeld-Wolfen, Germany

    Peter Lanzer

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Thiriet, M., Delfour, M., Garon, A. (2014). Vascular Stenosis. In: Lanzer, P. (eds) PanVascular Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-37393-0_32-1

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