Cardiac catheterization: consequences for the endothelium and potential for nanomedicine.

Focus Article

Cardiac catheterization: consequences for the endothelium and potential for nanomedicine Peter Sobolewski∗ and Miroslawa El Fray Cardiac catheterization results in interactions between the catheter and surfaces and the artery lumen, which is lined by the endothelium. These interactions can range from minor rubbing to severe mechanical injury. Further, in the case of radial access, even atraumatic interactions have consequences ranging from clinical complications, such as radial spasm and radial occlusion, to lasting endothelial cell dysfunction. These consequences may be underappreciated; however, endothelial cells play a central role in maintaining vascular homeostasis via nitric oxide production. Existing treatment paradigms do not address endothelial dysfunction or damage and, thus, novel therapeutic approaches are needed. Nanomedicine, in particular, offers great potential in the form of targeted drug delivery, via functionalized coatings or nanocarriers, aimed at increased nitric oxide bioavailability or reduced inflammation. © 2014 Wiley Periodicals, Inc. How to cite this article:

WIREs Nanomed Nanobiotechnol 2015, 7:458–473. doi: 10.1002/wnan.1316

INTRODUCTION

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hile overall cardiac catheterization procedure success rates are high (>90%),1,2 catheter and sheath contact with the artery lumen may have several adverse effects. Mishandling or an unexpected anatomical change can result in a severe impact on the vessel wall and mechanical trauma. However, due to the mechanosensitivity of the endothelium, even just an abnormal change in blood flow, let alone mild contact and rubbing between the catheter and endothelial cells, may also have a biological effect, such as an intracellular calcium response, which may ultimately lead to endothelial dysfunction. The recent and rapid adoption of radial access for both diagnostic and interventional catheter procedures,2–4 presents a further challenge due to the smaller diameter of the radial artery, as compared to the femoral artery, likely resulting in greater catheter–endothelium interactions. In fact, these interactions and the resultant endothelial cell dysfunction ∗ Correspondence

to: [email protected]

Division of Biomaterials and Microbiological Technologies, West Pomeranian University of Technology, Szczecin, Poland Conflict of interest: The authors have declared no conflicts of interest for this article.

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and damage are likely to be responsible for radial spasm and radial occlusion. These two complications, combined, have been identified as one of four ‘remaining challenges and opportunities for improvement in percutaneous transradial coronary procedures’ by Dr. Sunil Rao,5 an international expert in cardiac catheterization. Here, we will first provide an overview of the relevant endothelial cell biology, followed by a review of the consequences of catheter and sheath interactions with the endothelium, focusing in particular on the consequences of radial access. Finally, we will introduce potential nanomedicine approaches that may mitigate these interactions.

BACKGROUND: ENDOTHELIAL CELL BIOLOGY Beyond acting simply as a barrier between the blood and tissues, endothelial cells are able to sense chemical and mechanical signals and transduce them to the vessel wall, a process called mechanotransduction. Endothelial cells play a crucial role in maintaining vascular homeostasis, by regulating vessel tone, cell adhesion, and thrombosis, as well as inhibiting smooth

© 2014 Wiley Periodicals, Inc.

Volume 7, May/June 2015

WIREs Nanomedicine and Nanobiotechnology

Cardiac catheterization and the endothelium

muscle cell proliferation and secretion of extracellular matrix proteins.6 Central roles in the normal function of the endothelium are played by the endothelial surface layer (ESL) (and its integrity) and nitric oxide.

The Endothelial Surface Layer In vivo, the ESL, the blood-contacting surface of the endothelium, is composed of the glycocalyx and adsorbed plasma proteins.7 Of particular importance are the membrane bound and secreted polysaccharides, proteoglycans, and glycosaminoglycans that compose the glycocalyx,8,9 including heparan sulfate and hyaluronan. These components impart the endothelial cell surface a net negative charge and hydrophilic character. As a result, the ESL is a gel-like layer, ranging in thickness from tens of nanometers to a few microns,8 and plays an important role in modulating microvascular permeability and interactions of soluble plasma proteins, such as clotting factors and antioxidants.8 In addition, the glycocalyx has been implicated in mechanotransduction.10 Finally, the glycocalyx also serves an important mechanical role, being a major contributor to both the extremely low static and dynamic coefficients of friction (𝜇 ∼ 0.05),11 as well the low Young’s modulus (E ∼ 0.4 kPa)12 of the endothelium. Collectively, these properties result in the ESL being essential in maintaining vascular homeostasis.13 Recent research has correlated damage to the glycocalyx with cardiovascular risk factors,14 and, in fact, this has been postulated to be a cause, rather than consequence, of endothelial dysfunction and atherosclerotic progression.15,16 As a result, the ESL is emerging as an attractive cardiovascular diagnostic and therapeutic target,17,18 with specific strategies including the use of antioxidants and protease inhibitors or receptor antagonists, as well as maintenance of plasma protein levels, such as by albumin or hyaluronan infusions.

Nitric Oxide Originally identified as the endothelium-derived relaxation factor by Furchgott and Zawadzki in 1980,19 which was later clarified to actually be nitric oxide (NO) independently by Ignarro20 and Moncada,21 NO is an uncharged, free radical gas, produced by the nitric oxide synthase (NOS) family of proteins from L-arginine. NO can diffuse through cell membranes and bind with high affinity to heme-containing proteins or nitrosylate proteins. As a result, it exhibits complex, pleiotropic effects and is central to many aspects of physiology and pathology.22 In the vasculature NO, produced by endothelial cells via endothelial NOS (eNOS),23,24 mediates Volume 7, May/June 2015

vasodilation by diffusing to smooth muscle cells in the vessel wall and activating soluble guanylate cyclase (sGC),25 leading to increased production of guanosine 3′ ,5′ -cyclic phosphate (cGMP), a second messenger responsible for relaxation identified by Murad.26 Crucially, further research has revealed a host of additional roles for NO in maintaining vascular homeostasis. Rapidly, the antiplatelet role of NO was also identified,27 and it has since been demonstrated in detail that NO inhibits platelet adhesion, activation, and aggregation by cGMP-dependent and -independent pathways.28 Over time, the key role of NO as a regulator of endothelial function29 was also identified, including the inhibition of the activation of endothelial cells and modulation of their expression of cell adhesion molecules (CAMs). Importantly, NO bioavailability and signaling are very sensitive to the presence of superoxide, which reacts rapidly with NO producing peroxynitrite, a short-lived, strong oxidant. Such scavenging of NO may occur during periods of oxidative stress, such as during inflammation, as superoxide is produced as part of an inflammatory response. Further, several cardiovascular risk factors, including hypertension and diabetes, are associated with a pro-oxidant state and vascular superoxide can be produced by endothelial cells,30 such as by endothelial NAD(P)H oxidase (NOX4), xanthine oxidase, and even the eNOS enzyme itself, if it becomes uncoupled. NO scavenging by superoxide has been implicated in both platelet activation31 and endothelial dysfunction.32,33 As a result, there is potential for a vicious circle to occur, whereby oxidative stress results in reduced NO bioavailability, contributing to endothelial dysfunction and thus, further oxidative stress and reduced NO bioavailability.

Mechanotransduction Endothelial cells are capable of sensing the primary forces that they are exposed to as a result of blood flow34,35 : shear stress (in the direction of flow, tangential to the cell surface), normal stress (due to blood pressure), and circumferential stress (due to blood pressure). The fluid shear forces are four orders of magnitude lower than the cyclic pressure forces, which result in substantial deformation of the cell. Ultimately, both the direction and temporal gradients of these forces, in addition to their magnitude, serve to regulate endothelial function, including cell morphology, nitric oxide production, and gene expression.36,37 The precise mechanism of transduction of shear stress is complex and not fully understood.34,35,38,39 However, the key elements implicated include components of the glycocalyx,10 cell adhesion molecules,40


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G-proteins,41 G-protein coupled receptors,42 and cell–cell junctions.43 Despite their mechanosensitivity, endothelial cells are not harmed by high shear stress44 ; in fact, high positive, laminar shear stress is crucial for the maintenance of a homeostatic phenotype.45 However, large gradients in shear stress or turbulent flow do lead to damage and ultimately erosion of the endothelial cell layer.46–48 Further, disturbed flow leads to endothelial dysfunction and a pro-atherogenic phenotype, resulting in preferential development of atherosclerotic lesions near bifurcation and branch points, as well as regions of high curvature.49 As a likely consequence of their physiological transduction of shear and normal forces, endothelial cells are also sensitive to direct mechanical stimulation and deformation.50,51 Briefly, it has been demonstrated that glass micropipette contact causes a transient increase in intracellular calcium, which is dependent on an intact actin cytoskeleton, extracellular calcium, as well as the activity of a phospholipase. Intracellular calcium, in turn, is known to be a crucial regulator of many endothelial cell functions, including nitric oxide production,30 barrier function,52 and mitochondrial function.53 Similar observations have been made for the case gas embolism, where air bubble contact with endothelial cells in vitro triggers not only an intracellular calcium transient, but also mitochondrial dysfunction, via interactions with the ESL.54–56 Further, in a rabbit model, gas microemboli that did not obstruct blood flow, but simply passed through the microcirculation, still caused changes cerebral blood flow and depressed neural function.57 This latter finding strongly indicates that the air–liquid interface is able to elicit directly an endothelial cell response, resulting in abnormal signaling, dysfunction, or even cell death. Collectively, these findings indicate that even low-force interactions between endothelial cells and a liquid, a solid, or a gas bubble, that do not result in mechanical cell damage, can result in changes in signaling which can result in endothelial cell dysfunction.

Endothelial Cell Dysfunction Research over the past 10–15 years has led to a much greater clinical appreciation for the importance of endothelial function and an increased awareness that endothelial dysfunction is a hallmark of many classic cardiovascular disease risk factors,58–61 including diabetes, smoking, and obesity. Endothelial cell dysfunction is characterized primarily by an activation state resulting in reduced nitric oxide production, as well as a loss of anti-inflammatory, anti-adhesive, and 460

anti-proliferative signaling.32,59,60 As noted previously, due to their interplay with homeostatic nitric oxide, reactive oxygen species (ROS) play an important role as both initiators and consequences of endothelial dysfunction.32 Finally, endothelial cell dysfunction can result in not only a pro-atherogenic phenotype, but also mitochondrial dysfunction and, ultimately, apoptosis.53 While several methods exist for the clinical assessment endothelial cell function,61 measuring flow-mediated dilation (FMD) has remained the gold-standard62–64 since the development of the methodology in 1992.65 Briefly, this technique uses ultrasound to assess non-invasively the diameter of a conduit artery in response to a change in flow caused by the inflation and deflation of an occluding cuff downstream. The cuff is first inflated, occluding the artery, and then rapidly deflated, resulting in reactive hyperemia, an increase in blood flow through the artery to restore tissue oxygen. This increase in flow results in a corresponding increase in fluid shear stress, which is sensed by the endothelium and results in dilation of the artery via the release of nitric oxide and other mediators. Thus, this method relies upon endothelial mechanotransduction and NO production and provides an assessment of overall endothelial cell function.64

VASCULAR CONSEQUENCES OF CATHETERIZATION While access site and operator preference result in some variation,4,66 the process of percutaneous cardiac catheterization has changed little since Seldinger published his technique in 1953.67 Briefly, following access site preparation (including anticoagulation), a needle is used to puncture the vessel, followed by insertion of a guide wire, a sheath, and then ultimately advancement of the catheter. Immediately upon insertion of these foreign bodies into the blood, even in the presence of anticoagulation, interactions will occur between the material surface and the proteins in the blood.68 The exact nature of the interface, charge, wettability, will determine the specific proteins and interactions that occur, such as changes in conformation. In general, hydrophilic surfaces may result in a more favorable protein adsorption profile. The combination of the initial vessel injury combined with the physiochemical properties of the material surface and protein adsorption will then drive the initial acute inflammatory response.69 Importantly, even diagnostic cardiac catheterization, in the absence of gross mechanical trauma, results in a systemic inflammatory response (similar to that as PCI), as indicated by an increase





in the inflammatory biomarker C-reactive protein.70 While a complete review of the foreign body response is beyond the scope of this review, the increase in oxidative stress is likely to contribute to endothelial dysfunction. As the catheter is advanced, it is inevitable that there will be contact between the catheter surface (or tip) and the vessel lumen. A range of mechanical interactions can be expected, from sliding and rubbing, to poking or prodding (Figure 1). Rarely, in the case of mishandling or an unexpected anatomical feature, these interactions can result in a severe impact on the vessel wall and mechanical trauma, up to and including dissection or perforation of the vessel wall.71 The magnitude of the catheter–lumen interactions will have a profound effect on the severity of the vessel injury. Importantly, patients undergoing cardiac catheterization as a result of cardiovascular disease may have pre-existing damage to their glycocalyx, making their endothelium potentially more vulnerable to damage by the catheter or sheath.

Elastic lamina rupture Medial injury

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Elastic lamina

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Mechanical Vessel Injury It is well established that rubbing the luminal surface of a blood vessel results in denudation, removal of the endothelial cell layer. For example, the use of a balloon catheter to denude an artery segment has long been used as a model of arterial injury and intimal thickening.72,73 Following the injury, platelets and leukocytes are recruited rapidly to the injury site. Then, within 24 h, smooth muscle cells (SMC) of the media begin to replicate, due to a combination of growth factor release from injured SMC, access to blood-born growth factors, and lack of inhibitory endothelial cell signaling,74–76 including nitric oxide.77 Following this initial response, additional SMC migration and proliferation occurs, along with the deposition of extracellular matrix proteins, ultimately resulting in the formation of neointima and a substantial stenosis of the artery. In fact, it is this injury response that has led to the use of stents (and later drug-eluting stents), instead of balloon angioplasty alone. Importantly, in the balloon catheter injury model, the degree of injury correlates with the inflation pressure of the balloon.78 Neointima formation correlates strongly with rupture of the elastic lamina,79 the elastin layer separating the endothelium from the smooth muscle of the media, which would also result in medial injury. Additionally, such severe balloon injury resulted in lasting denudation of the artery.80,81 By comparison, and no formation of neointima was observed when a deflated balloon Volume 7, May/June 2015

Damaged EC

Denudation

FIGURE 1 | Catheter–lumen interactions. (a) Severe artery wall trauma resulting from poking or prodding with the catheter, including damage to the elastic lamina and medial injury. (b) Mild intimal injury caused by rubbing, resulting in endothelial damage and denudation. Note: Damaged or activated endothelium is indicated by reducing the thickness of the ESL and tinting it red.

was used.78 Further, an alternate, mild method of denudation, using a nylon suture loop, resulted in no medial injury, complete re-endothelialization, and reduced neointimal formation82 ; neointima was only observed in regions where denudation lasted longer than 7 days. We conclude that these two models (balloon and nylon loop) likely cover the range of vascular injuries likely to occur during catheter advancement: severe mechanical trauma (Figure 1(a)), with damage to the elastic lamina, and mild intimal injury (Figure 1(b)), resulting in transient denudation followed by complete re-endothelialization and no neointimal formation. The latter is particularly likely to be the case during atraumatic catheterization procedures and femoral access procedures, where the artery diameter greatly exceeds the guide catheter and sheath diameter. However, in the case of radial access, the radial artery is typically very close in diameter to the catheter and sheath; thus, one would predict


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the occurrence of more severe consequences for the endothelium and artery wall, more akin to balloon injury, potentially including lasting denudation and neointimal formation.

Activated endothelium, ROS↑NO↓

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TRANSRADIAL ACCESS: CONSEQUENCES FOR THE ENDOTHELIUM Since being introduced in 1989,83 radial access has seen increasing use for cardiac catheterization procedures,2 particularly in Europe and Asia, where it accounted for 29 and 42% of percutaneous coronary intervention (PCI) procedures, respectively, in 2009. In the United States, radial access is also being rapidly adopted for PCI, with the percentage of radial access procedures increasing from sub-2% in 2007 to exceeding 16% in 2012.3 Over the past 15 years, a number of clinical trials1,84,85 have demonstrated the safety and efficacy of radial access, as well as its cost effectiveness.86 Finally, in 2013, the European Association of Percutaneous Cardiovascular Interventions and Working Groups on Acute Cardiac Care and Thrombosis of the European Society of Cardiology released a consensus statement recommending radial access as the default approach.4 The major benefits of radial access, as compared to femoral access, are reduced access site complications, especially bleeding, as well as a trend toward lower mortality.87 Further, patients in the RIVAL trial, which compared radial and femoral access, preferred radial access, indicating greater comfort.1 However, due to the small diameter of the radial artery, as compared to the femoral artery, some problems remain,5,88 including spasm and even occlusion of the radial artery.

Radial Spasm Radial spasm involves the excessive constriction of the radial artery, caused by smooth muscle contraction,89,90 which occurs with an incidence rate of 4–20%. Spasm results in patient discomfort and pain, ultimately accounting for over 30% of procedure failures.91 Major predictors of radial spasm include factors relating to guide catheter or sheath and radial artery diameter, diabetes, and reduced FMD.92–94 While the mechanism responsible for spasm is not established,90 these predisposing factors suggest the involvement of endothelial dysfunction or denudation (Figure 2). The resultant loss of vasodilating NO signaling, combined with the potential oxidative stress response likely results in the observed vasoconstriction. 462

Vasoconstriction

Media

Elastic lamina

Denudation, NO↓

FIGURE 2 | Catheter-induced spasm. At top, mild catheter–lumen interactions have caused endothelial activation and dysfunction, leading to an increase in ROS and a reduction in NO bioavailability. At bottom, more severe intimal injury caused by rubbing, results in denudation, and a loss of endothelial NO production. Note: Damaged or activated endothelium is indicated by reducing the thickness of the ESL and tinting it red. Reduced NO bioavailability in the media and consequent vasoconstriction is indicated by orange highlighting.

Current approaches to preventing radial spasm include the use of vasodilating cocktails,4 aimed at pre-dilating and maintaining the dilation of the artery. At present, various combinations of pharmaceuticals are employed at the discretion of the operator, including nitroglycerin and calcium channel blockers, and, more recently, a nitric oxide donating pro-drug.95 This approach has been successful in reducing the incidence of spasm, although the systemic administration of such drugs does carry the risk of hypotension. More recently, hydrophilic coatings,92,96–98 typically water-activated hydrogels, such as poly(vinylpyrrolidone), have been introduced, aimed at improving catheter and sheath lubricity. These methods have also proven effective at reducing the incidence of spasm and improving patient comfort, however the use of hydrophilic sheaths does not appear to prevent the reduction in FMD, which took 3 months to recover.99 Further, the use of certain hydrophilic coatings (those manufactured by Cook,100,101 in particular) has been associated with the formation of sterile granulomas and abscesses.102–106

Radial Occlusion Radial occlusion is a post-procedure complication occurring 5–12% of the time, that is considered to not have direct clinical complications in the case of good double blood supply (as assessed by the Allen’s test).107,108 However, a 2010 survey109 indicates that radial patency is not assessed before discharge in a majority of cases. In fact, a recent ultrasound study110 suggests that occlusion incidence rates may be as high





as 30% with 6F sheaths and that the clinical significance may be underestimated. In this study, over 40% of patients with radial occlusion developed symptoms immediately, with another 7% post-discharge onset of symptoms. Further, the observed a 30-day persistence of occlusion in 2–5% of cases108 is troubling. As a result, radial occlusion cannot be ignored,5 as it also complicates future radial access or use of the radial artery as conduit for coronary bypass surgery. The mechanism responsible for radial occlusion remains unclear; a combination of artery wall injury and intimal medial thickening, as well as thrombosis appear to play a role.111 The ratio between the catheter sheath and the radial artery is a significant risk factor112 and the use of 5F sheaths has been demonstrated to reduce incidence by over 50%.110 However, the use of hydrophilic sheaths did not markedly influence the incidence of occlusion92,97 and a recent optical coherence tomography study indicates that, even when utilizing hydrophilic sheaths, intimal, and medial injury of the radial artery occurs in one third and one tenth of patients, respectively.113 Collectively, these findings suggest that radial occlusion may be the result of more severe artery trauma, including denudation and damage to the elastic lamina, resulting in remodeling and neointimal formation. Additionally, given the important anti-thrombotic role of healthy endothelial cells,114 it is likely that endothelial cell dysfunction plays an important role in radial occlusion.

Endothelial Dysfunction, Damage, and Denudation The etiology of both radial spasm and occlusion is likely to involve endothelial cell dysfunction, damage, or denudation. However, while these two complications have been well studied and well publicized, the incidence of endothelial dysfunction following transradial catheterization has not received as much attention, despite a number of studies over the past 10+ years documenting changes in radial morphology and endothelial function.99,115–125 Several of these studies have documented marked defects in radial artery FMD,99,117,120–122 indicating endothelial dysfunction, lasting several weeks or even months. Further, ultrasound studies have noted incidence of radial artery intimal hyperplasia and stenosis,115,116,118,119,123 which correlated with the use of larger catheter and sheath diameters, especially those exceeding the diameter of the artery lumen.115,116 Similar observations of intimal hyperplasia have been documented by a histopathology study utilizing 5F hydrophilic sheaths126 and an optical coherence tomography study.127 Collectively, these Volume 7, May/June 2015

findings are consistent with endothelial denudation and even medial injury triggering remodeling of the radial artery. Most of these studies examining radial artery damage following transradial catheterization have been motivated by the possible need of the radial artery as a vascular graft in coronary bypass surgery. However, there is also evidence of reduced FMD following transradial catheterization beyond the area affected by the sheath.121,122 In particular, reduced FMD was observed in the brachial artery 24 h after radial catheterization121 and was particularly pronounced in smokers or patients requiring more than three catheters, despite the brachial arteries in this study having an average diameter (4.4 mm) well in excess of the 5F diameter catheter that was used. It is important to note that this observed endothelial dysfunction upstream from the access site is likely the result of a combination of inflammatory response and catheter–lumen interactions. On the other hand, a recent study comparing radial and femoral access125 found endothelial cell dysfunction in the ipsilateral hand, downstream of the access site. This dysfunction could only be mediated by a combination of systemic inflammatory response and soluble factors released as part of upstream vascular injury. In conclusion, a developing body of research indicates that cardiac catheterization may have far-reaching endothelial consequences, which may have hitherto been underappreciated, particularly in patients with existing endothelial dysfunction. Given the previously noted interplay between endothelial cell dysfunction and cardiovascular risk factors, these potentially lasting vascular effects of cardiac catheterization procedures are concerning and existing paradigms do not appear to have the potential to address this successfully. Reducing catheter and sheath diameters appears to be the best available option aimed at reducing the vascular sequelae of cardiac catheterization. However, there are practical limits set by the need for appropriately sized lumens for passage of devices and flow of contrast agents. There is some potential for novel composite materials to enable a reduction in catheter and sheath wall thickness while maintaining the requisite mechanical properties, however modern catheter wall thickness is already on the order of 100 μm, so any further gains are likely to be minimal. As a result, the current state-of-the-art involves sheathless guide catheters,128–135 which allow for a larger catheter lumen and can also have hydrophilic coatings. However, the mixed results with hydrophilic coatings (improved patient comfort, reduced incidence of spasm, but not radial occlusion and endothelial


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dysfunction) indicate that improving lubricity alone is not sufficient and that novel approaches addressing the mechanism of arterial injury and resultant remodeling are necessary.

NANOMEDICINE: A NEW THERAPEUTIC PARADIGM

Vasolidation

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Nanotechnology as a field was forecast by Feynman in 1959,136,137 coined as a term by Taniguchi in 1974,138 popularized by Drexler in the 1980s,139,140 and, arguably, enabled by Binnig in the 1980s, with the development of scanning tunneling microscopy141 and later atomic force microscopy.142 Importantly, at the nanoscale there is a convergence between material, form/structure, and function and this is precisely the scale that biology operates on, a fact recognized by Feynman. However, from the present point of view of nanomedicine,143 the application of nanoscale materials and technologies to the diagnosis or treatment of disease, the origins of nanotechnology may more accurately lie in the work on colloids by Zsigmondy144 and surface chemistry by Langmuir145 in the early part of the 20th century. Regardless of origin, recent advances in nanotechnology, providing new tools to manipulate and characterize materials at the nanoscale, are opening up new diagnostic and therapeutic avenues. In fact, a recent study has identified over 200 nanomedicine products in various stages of clinical study and approval.146 One particularly promising application of nanotechnology, has been in the area of drug delivery,147 with nanotechnology approaches enabling targeting of drugs, as well as facilitating the delivery of previously challenging molecules. Of particular relevance to the challenge discussed here, are NO donor drugs, which have been developed since the 1980s,148 but their transition of these molecules to the clinic has been limited, due to problems with toxicity, stability, and delivery. During cardiac catheterization, endothelial cell dysfunction, as well as pro-oxidant state, will result in reduced NO bioavailability and, consequently, reduced anti-inflammatory, anti-adhesive, and anti-proliferative signaling. Thus, it is natural to target augmentation or restoration of NO bioavailability as a means of ameliorating the vascular sequelae of cardiac catheterization, as this approach has also been proposed to combat intimal hyperplasia.149 Fortunately, recent developments in nanotechnology offer a number of new delivery platforms150 and two synergistic approaches will be discussed here: functional coatings and nanocarriers. 464

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FIGURE 3 | NO-functionalized, hydrophilic catheter coating. Hydrophilic, NO releasing coating increases NO bioavailability leading to vasodilation (blue highlighting) and reduced intravascular inflammation and endothelial activation.

Functional Coatings Both the acute inflammatory response and vascular injury caused by cardiac catheterization are a direct result of interactions between the surfaces of catheters and sheaths and body tissues. The current clinical experience with hydrophilic coatings provides clear guidance that modifying these surfaces can have a positive effect. Here, we propose moving beyond existing coatings that serve a primarily lubricious function and into functional coatings that can act as a drug delivery platform for nitric oxide (Figure 3). Polymer coating formulation for NO delivery is an active area of research,150–152 including applications in extracorporeal circuits153 and catheters for intravascular/indwelling use.154 Further, a NO eluting sheath has already provided positive results in an animal study.155 However, this study appears to ignore some lessons from the existing coatings used clinically, such as the positive patient response to hydrophilic coatings92 and the potential for fragments of the coating to remain in the body and illicit an immune response.103 Thus, a novel catheter and sheath coatings should remain hydrophilic and ideally be biodegradable or, at least, form a single, thin, well-bonded layer. Here, two recent research developments will be presented, with these properties in mind. Biopolymers fulfill these criteria and have already been used as hydrophilic coatings for medical devices.98 Dextran, a natural, biodegradable, hydrophilic polymer, is FDA approved as a plasma expander and has recently been demonstrated as a wear-resistant coating for blood-contacting polymer materials,156 resulting in reduced activation of the acute inflammatory response. Recently, a NO donating dextran has been developed.157–159 This new system involves the S-nitrosation of dextran,





yielding a thiol-based NO delivery mechanism, while minimizing the formation of N-nitrosamines, which can be toxic. In plasma, the modified dextran steadily released NO over the course of 2 h, a reasonable time scale for cardiac catheterization procedures. Finally, in in vitro plasma and whole blood assays, this NO was bioavailable, resulting in marked antithrombogenicity. Thus, combining this novel dextran S-nitrosation process with the polymer coating strategy can yield hydrophilic, NO-donating coatings with great potential for catheter and sheath applications. An alternate, novel coating system can also be considered,160 which leverages the strong adhesive properties of catecholamine groups to form poly(dopamine) or poly(norepinephrine) coatings that can act as NO depots. These hydrophilic coatings can be applied to a variety of materials, ranging from metals to ceramics to polymers, and, in the case of poly(norepinephrine), can be ultra-smooth and as thin as 12 nm. Despite such thinness, the poly(norepinephrine) coating could store nearly 2 μmol NO/cm2 and release it with a half-life of 4 h. One possible concern with this system, however, is the fact that dopamine and norepinephrine, in particular, are vasoactive, potentially causing vasoconstriction via 𝛼 1 adrenergic receptors. Clearly, the wear resistance and potential vasoactivity of these coatings need to be examined before their full potential can be assessed.

Nanocarriers Nanocarriers offer great potential for drug delivery, as they can improve drug stability, solubility, extend circulation time, and provide means of targeting. With regard to the vascular consequences of cardiac catheterization, nanocarriers facilitate several possible therapeutic approaches, such as improved intravascular delivery of NO or targeted delivery of drugs to endothelium or injured artery (Figure 4). Many nanocarrier solutions, ranging from liposome/micelle-based to polymeric or inorganic, have been designed to address the delivery problems of NO.150 The optimal modality remains to be determined, as efficacy and safety studies are ongoing. However, NO nanocarriers have the potential to be integrated as part of vasodilatory, anti-spasm cocktails, improving efficacy compared to existing clinical options, such as nitroglycerin and, in particular, molsidomine, a drug that may also release superoxide in addition to nitric oxide. Alternately, NO nanocarriers could be utilized to provide a post-procedure, sustained release of a lower dose of NO, in order to restore NO bioavailability compromised by the inflammatory response and vascular injury. Volume 7, May/June 2015

Targeted nanocarrier

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FIGURE 4 | Nanocarrier approach to mitigating the consequences of catheter–lumen interactions. Targeted nanocarriers (dark blue) can be used to deliver drugs (NO, anti-oxidants, etc.) to injured, denuded areas or to activated endothelium. Non-targeted carriers (light blue circles) can be used to increase NO bioavailability.

However, the perhaps greater potential impact of nanocarriers lies in the ability to leverage targeting ligands in order to maximize the therapeutic dose of a drug at the site of need. For the case of cardiac catheterization induced vascular injury, several possible targets exist. First, one could target the endothelium itself, perhaps prior to the procedure, in order to deliver a protective payload, for example antioxidants, in order to mitigate any deleterious effects of the initial inflammatory response or endothelial dysfunction. This is an on-going area of research,161 but a recent study has demonstrated the great potential of this approach.162 In this work, nanocarriers loaded with super oxide dismutase, an antioxidant enzyme that breaks down superoxide, or catalase, an antioxidant enzyme that breaks down hydrogen peroxide, were effectively targeted to endothelial cells via antibody against PECAM-1, a cell adhesion molecule highly expressed by all endothelial cells. These two formulations were protective in two different mouse models of acute inflammation, endotoxin challenge and cytokine activation. A similar approach could be used to target activated, potentially dysfunctional endothelial cells, by replacing the PECAM-1 targeting antibody with antibody against a cell adhesion molecule that is upregulated by pro-inflammatory cytokines, such as ICAM-1 or VCAM-1. Importantly, any targeted antioxidant delivery approach could be synergistic with attempts to increase NO bioavailability via NO delivery, such as by functional coatings or nanocarriers. An alternative approach involves targeting the locations of vascular injury, by taking advantage of the fact that in areas of denudation SMCs and the extracellular matrix are exposed, revealing potential


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molecular targets that are not available to the blood in healthy vessel segments with intact endothelium. For example, both 𝛼 v 𝛽 3 -integrin and collagen targeted nanocarriers have been utilized to facilitate magnetic resonance imaging of vascular injury following balloon injury.163 This approach was extended to utilize the nanocarriers to deliver the anti-proliferative drug rapamycin, in order to reduce SMC proliferation and neointimal formation.164 Alternately, one could deliver NO nanocarriers via similar targeting ligands in order to restore homeostatic NO bioavailability in denuded areas lacking endogenous NO production by the endothelium. Recently, a hybrid approach has been proposed to target nanocarriers to sites of vascular injury by mimicking the binding of platelets.165 In this case, nanocarriers loaded with dexamethasone, an anti-inflammatory steroid, were decorated with two ligands: glycoprotein1b, a platelet surface ligand for von Willebrand Factor (vWF) and P-selectin, and trans-activating transcriptional (TAT) peptide, a cell penetrating peptide. Glycoprotein1b acts as the targeting ligand, facilitating nanocarrier binding to denuded areas via vWF and activated endothelium via P-selectin, while TAT improves nanocarrier uptake. In a rat carotid balloon injury model, local infusion

of these platelet-like nanocarriers resulted in reduced neointima formation. A similar approach could be adapted to deliver other therapeutic agents, such as NO or antioxidants.

CONCLUSION The development and increasing adoption of radial access for catheterization presents new clinical challenges. The diameter of the radial artery restricts the possible catheter and sheath diameters, but procedural demands require the use of catheters with large lumens. As a direct consequence, the catheters and sheaths used are very close in diameter to the internal diameter of the artery (and can even exceed it), resulting in greater interactions with the endothelium and artery wall. These interactions drive the clinical complications of radial access: spasm and occlusion. Despite high procedure success rates (>90%), the incidence of lasting endothelial dysfunction or artery damage may be underappreciated. Nanomedicine offers novel therapeutic strategies to address these problems, including coatings aimed at not just increased lubricity, but also biofunctionalization, and targeted drug delivery, aimed at increased NO bioavailability or reduced inflammation.

ACKNOWLEDGMENTS This work was supported by EU Marie Curie Industry-Academia Partnerships and Pathways: UNITISS, Understanding Interactions of Human Tissue with Medical Devices, FP7-PEOPLE-2011-IAPP/286174. Additionally, the authors wish to thank Judith Kandel, David M Eckmann, MD PhD, Steven Franklin, PhD, and Jarosław Goracy, MD for helpful discussion and Karen Sobolewski for help with illustration and figure preparation.

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Preparation for cardiac catheterization.

Caring for cardiac catheterization patients.

Anesthesia for cardiac catheterization procedures.

Interventional catheterization for congenital cardiac defects.

Ambulatory anesthesia for the cardiac catheterization and electrophysiology laboratories.

A review of sedation scales for the cardiac catheterization laboratory.

A comparison of radial and femoral access for cardiac catheterization.

Alfentanil sedation for cardiac catheterization of children with Fontan shunts.

Multimodality 3-dimensional image integration for congenital cardiac catheterization.

Using central venous catheter for suprapubic catheterization in cardiac surgery.

Value of right-sided cardiac catheterization in patients undergoing left-sided cardiac catheterization for evaluation of coronary artery disease.

Nanomedicine for respiratory diseases.

Incidence of and risk factors for catheterization-induced complete heart block in the pediatric cardiac catheterization laboratory.

Cardiac catheterization laboratory survey: 1990. Society for Cardiac Angiography and Interventions, Laboratory Performance Standards Committee.

Propofol in cardiac catheterization.

Propofol in cardiac catheterization.

Mobile cardiac catheterization laboratories. Society for Cardiac Angiography and Interventions Laboratory Performance Standards Committee.

Nanomedicine for global health.

Endothelium, endocardium, and cardiac contraction.

Cardiac catheterization 1990: a report of the Registry of the Society for Cardiac Angiography and Interventions (SCA&I).

Diagnostic Cardiac Catheterization in the Pediatric Population.

Minimizing risk in the cardiac catheterization laboratory.

Theranostic nanomedicine for cancer detection and treatment.

Vascular complications of cardiac catheterization.