The Changing Face of Vascular Interventional Radiology: The Future Role of Pharmacotherapies and Molecular Imaging
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- Tapping, C.R. & Bratby, M.J. Cardiovasc Intervent Radiol (2013) 36: 904. doi:10.1007/s00270-013-0621-3
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Interventional radiology has had to evolve constantly because there is the ever-present competition and threat from other specialties within medicine, surgery, and research. The development of new technologies, techniques, and therapies is vital to broaden the horizon of interventional radiology and to ensure its continued success in the future. In part, this change will be due to improved chronic disease prevention altering what we treat and in whom. The most important of these strategies are the therapeutic use of statins, Beta-blockers, angiotensin-converting enzyme inhibitors, and substances that interfere with mast cell degeneration. Molecular imaging and therapeutic strategies will move away from conventional techniques and nano and microparticle molecular technology, tissue factor imaging, gene therapy, endothelial progenitor cells, and photodynamic therapy will become an important part of interventional radiology of the future. This review looks at these new and exciting technologies.
KeywordsClinical practiceExperimental IRImagingChemoembolizationCombined treatmentsDiagnosticEmbolizationLaser treatmentUltrasound
Interventional radiology (IR) is the field of image-guided microinvasive therapy. Its foundation were established many years ago when Dotter described a new technique of transluminal treatment of atherosclerotic obstruction . It currently plays important roles in the diagnosis and management of cardiovascular disease, cancer, trauma, as well as many others. In the future, image-guided IR will link the skills of invasive catheter-based therapies with new disease prevention strategies and therapies. Cardiovascular risk factor prevention also will play a large part in the future and reduce the number of patients with atherosclerotic and aneurismal disease. This will shift the emphasis of IR to involve embolization, chemoembolization, gene therapy, tumour ablation, and MR guidance. Research itself will change to focus at the molecular level as well as concentrating more on patient choice, tailored strategies, and their experience. The future of IR will be steered by the results of research in large part by quality of life outcomes and healthcare economics. The competition from surgical and medical specialties as well as that from research will mean that the development of new techniques involving imaging and therapeutic strategies will allow the continued success of IR. A willingness to embrace these new technologies and to take an active role in research will be an essential part of IR in the future [2, 3].
This article takes a look at some of the potential developments that will affect our practice in the future.
Cardiovascular Risk Factor Prevention
High levels of low-density lipoprotein cholesterol (LDL) have been shown to be one of the strongest risk factors for progression of atherosclerosis, whereas high-density lipoprotein cholesterol (HDL) prevents the progression of atherosclerosis. Statins have been shown to decrease LDL cholesterol concentration and induce regression of atherosclerotic plaque in the carotid artery [4, 5]. Adding ezetimibe (a selective cholesterol-absorption inhibitors) to the highest dose simvastatin regime has been shown to further reduce LDL and C reactive protein but did not show a decrease in carotid intima-media thickness (enhance study) . Lower-dose statin regimes in patients with familial hypercholesterolaemia also have shown a reduction in coronary heart disease and myocardial infarction, with the risk of myocardial infarction being reduced to that of age-matched patients in the general population .
It may be upregulated by LDL/oxLDL or proinflammatory cytokines in endothelial cells .
Other proatherosclerotic agents have provided a link between hypertension and atherosclerosis. Angiotensin-II  and endothelin-I  (potent vasoconstrictors) have been shown to increase the expression of LOX-1 and LDL/oxLDL uptake into endothelial cells .
Mice overexpressing LOX-1 also showed an increase in atheroma-like lesions following a high fat/cholesterol diet  and LOX-1 knockout mice on a high cholesterol diet have shown reduced formation of atherosclerotic-like lesions, lower intimal thickness, lower levels of proatherosclerotic, and pro-oxidative signalling and inflammatory responses .
LOX-1 also is found in macrophages and smooth muscle cells (SMC) in the intimae of advanced atherosclerotic plaques in humans .
LOX-1 also has been shown to promote vascular smooth muscle proliferation, the proliferation of foam cells, ligand binding in aged and apoptotic cells, and promoted the adhesion of platelets, leukocytes, and bacteria .
There are of course other receptors involved in the process, although these are not yet well understood (SR-A1/II, CD36, SR-B1, microsialin/CD68, and SREC also have been implicated .
There are therapeutic means to reduce LOX-1 expression and atherosclerosis. Pretreating endothelial cells with statins reduced oxLDL-induced LOX-1 expression and the upregulation of LOX-1 by a high cholesterol diet was reduced with losartan . In the recent endothelial protection, AT1 blockade and cholesterol-dependant oxidative stress trial (EPAS) statin and AT1 blockade therapy independently and in combination improved the endothelial function of internal mammary arteries of patients with coronary artery disease undergoing elective coronary artery bypass grafting . High levels of LDL reduce the number and function of endothelial progenitor cells (EPC) and oxLDL can induce senescence and impaired adhesion, migration, and tube-forming capacities of EPC . Furthermore, simvastatin has been shown to increase the mobilisation of EPC from bone marrow , and injection of HDL into patients with type II diabetes increased the number of EPC .
It is not currently possible to determine accurately the reduction of patient numbers to the IR department due to statin therapy the studies assessing the affect of statins on AAA have had a small sample size and limited follow-up period. An adequately powered randomized study with long-term follow-up of small AAA should be performed to clarify the effect of this agent.
Beta-Blockers and Angiotensin-Converting Enzyme Inhibitors
The use of beta-blockers (β-blockers) and angiotensin-converting enzyme inhibitors (ACEi) in controlling cardiovascular risks factors in the general population is well established. However, the use of these medical therapies in certain syndromes is less well established. Marfan’s syndrome (MFS) (tall stature, arachnodactyly, joint hypermobility, skeletal abnormalities, lens subluxation, and mitral valve prolapse) and the recently characterised Loeys-Dietz syndrome (hypertelorism, bifid uvula/cleft palate or both, and generalised arterial tortuosity with aneurysms and dissections) patients have a high risk of aortic dissection and aneurysms.
Marfan’s syndrome is an autosomal dominant connective tissue disorder caused by mutations in FBN1. This is the gene responsible for encoding fibrillin 1, a key component of the extracellular matrix and a negative regulator of transforming growth factor-β (TGF-β), which contributes to matrix metalloproteinase (MMP) activation and extracellular matrix degradation . Following a trial of 70 patients with MFS, 32 given propranolol and 38 control patients, β-blockers have been the standard treatment for MFS. These decrease aortic wall stresses, however, recently the angiotensin system has been implicated in affecting aortic stiffness, dilatation, and rupture. In fibrillin-1–deficient mice the activation and signalling via TGF-β was blocked by the AT1 (angiotensin II type I receptor) antagonist losartan preventing aortic aneurysm formation . Furthermore, AT2 (angiotensin II type II receptor) is expressed more in MFS aortas and is associated with cystic medial degeneration, which contributes to rupture . ACEi and AT2 antagonism also decrease vascular smooth muscle cell apoptosis in vitro from aortic cells cultured from MFS patients . ACEi are known to reduce large artery stiffness  and perindopril along with beta-blockers has been shown, in a small randomized, controlled trial to reduce aortic stiffness and diameter . The mechanism for this is likely to occur via reduced TGF- β and MMP-2 and MMP-3 secondary to reduced AT1 signalling and reduced AT2 signalling may help by limiting cystic medial degeneration. The benefits of ACEi on large artery properties are well established, but whether perindopril or other ACEi are more effective in not yet known [29–31]. If further larger trials agree with these findings that medical therapies protect the aorta they might gain wide acceptance as prophylactic therapy in these patients reducing the need for stent insertion by IRs.
Loeys-Dietz syndrome patients have mutations in TGF-β receptors 1 and 2 and are at the severe end of a continuum of clinical features. At the mild end of this group are patients with a phenotype similar to that of MFS or familial thoracic aneurysm and dissection . These patients are usually treated with β-blockers, exercise restriction, frequent cardiovascular imaging, and prophylactic surgical repair (aortic root >5.0 cm or in children when aortic diameter exceeds 1 cm growth in 1 year). Patients with Loeys-Dietz syndrome tend to have earlier cardiovascular events, often in childhood and, have a shorter median survival of 37 versus 70 years for MFS . The severity of craniofacial dysmorphism in Loeys-Dietz syndrome is predictive of age at first cardiovascular event . Clinical trials are required to assess the potential for ACEi therapy in these patients as well as the optimum timing of interventions.
The nonselective β-blocker propranolol has been shown in children to reduce infantile haemangioma. Propranolol was given to nine children who had disfiguring infantile capillary haemangioma. In all patients, 24 h after the initiation of treatment there was a change in colour of the lesions from intense red to purple and was associated with a palpable softening of the lesion. After these initial changes, the haemangioma continued to regress until they were nearly flat, with residual skin telangiectasias. Ultrasound examinations in five patients showed an objective regression in thickness associated with an increase in the resistive index of vascularization of the hemangioma , reducing the need for intervention or surgical management. Regulators of haemangioma growth and involution are poorly understood. However, two major proangiogenic factors are involved: basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF); histologic studies have shown that both endothelial and interstitial cells are actively dividing in this phase . Potential explanations for the therapeutic effect of propranolol are vasoconstriction and decreased expression of VEGF and bFGF genes through the down-regulation of the RAF–mitogen-activated protein kinase pathway  and the triggering of apoptosis of capillary endothelial cells .
Mast Cell Degranulation
Mast cells (MCs) are proinflammatory cells that play important roles atherosclerosis and abdominal aortic aneurysm (AAA) growth. The presence and function of MCs in atherosclerotic lesions has been thoroughly studied in human specimens but their role in AAA growth was recognized only recently. Via numerous activation pathways, MCs release a variety of mediators, including histamine, inflammatory cytokines, chemokines, growth factors, proteoglycans, and proteases to activate neighbouring cells, degrade extracellular matrix proteins, process latent bioactive molecules, promote angiogenesis, recruit additional inflammatory cells, and stimulate vascular cell apoptosis . These activities associate closely with medial elastic breakdown, medial smooth-muscle cell loss and thinning, outer media and adventitia inflammation, aortic wall expansion, endothelium erosion, and eventual rupture and thrombosis. Genetic deficiency of MCs, pharmacological inhibition of MC degranulation, absence of MC-specific chymase and tryptase, or inhibition of these proteases, can effectively attenuated or abolished experimental AAA growth . These observations offer new opportunities to prevent or slow AAA growth in humans. Currently, mast cell inhibitors are used in the treatment of allergies, such drugs may be of value in the future for inhibiting growth of small AAAs without need for surgical repair reducing the need for endovascular aortic repair.
Molecular Imaging and Therapies
Molecular imaging is an in vivo imaging technology capable of depicting biologic events at the cellular and molecular level . Whilst it has become of significant interest to diagnostic and interventional radiologists alike it has currently several limitations, which include short light-penetration capability of molecular optical imaging, insufficient visualization of small and deep-seated targets with molecular MR imaging performed by using surface coils, and the physiologic excretion of some targeted imaging and therapeutic probes by the kidneys and liver. However, these techniques are of great interest and have shown significant early promise.
Nano-Microparticles and Molecular Technology
Nano- and microparticles formed from imaging-detectable biomaterials have allowed the production of exciting new types of imaging and therapeutic agents. They combine three functions in one package: imaging agent, target probe, and drug/gene carrier . These particles include liposomes (phospholipids) with an internal space , emulsions (oil and water mixtures) stabilised by surfactants , polymeric spheres (polymers) , and microbubbles made from albumin or charged lipid, which resonate and are visualised under an US probe . Newer technologies include quantum dots (semiconducting nanocrystals), which have fluorescent properties at different wavelengths , aquasomes (core of nanocrystalline calcium phosphate) for drug and antigen delivery , gold nanoparticles, which produce improved contrast at CT , and metal nanoshells, which have a thin, conductive metal layer used for infrared contrast agent for optical imaging . There are no standardised criteria for defining nano and microparticles; however, nanoparticles are typically 5–700 nm in diameter whilst microparticles are larger at approximately 3 μm in diameter [43, 45]. Their imaging capabilities are due to their construction along with imaging contrast agents. For example, by combining a microparticle with paramagnetic gadolinium in MR imaging allows its detection and localisation .
Modification of the surface of these particles by the attachment of specific ligands allows site specific localisation of targets and permits assessment of functionality at a molecular level (molecular imaging). The interaction of these ligands to receptors (corresponding target molecule usually a cell surface receptor) to form an antigen-antibody pair complex is specific and allows accurate localisation at the site of interest.
Therapeutic agents can be attached to the surface of the particle, incorporated into its structure, or encapsulated within it . Their small size allows them to gain access to small capillaries delivering a sustained release of drug directly to the target site (target-specific therapy ) whilst reducing systemic side effects . The DC bead (Biocompatibles) has been designed to be a transarterial chemoembolization (TACE) product, which has been shown to improve local drug delivery significantly, without systemic side effects in the treatment of HCC and colonic liver metastases .
Applying nano- and molecular therapies to interventional imaging and techniques will allow assessment of the distribution and localisation of therapies at specific targets, increase the local effect of therapeutics, and allow the monitoring of the effect of the delivered product at the site and reduce side effects and the need for more invasive interventions.
Knowing how much and where the product has been delivered by using traditional image-guided interventional techniques will ensure the success of these procedures. New techniques also will play their role, for example, using US to monitor vascular gene delivery. In this technique, the product was infused by a catheter into the arterial walls and the echogenic gene-carrying particles were monitored . Combining drug-carrying nanoparticles with arterial stent placement also has been shown to reduce in-stent restenosis [56, 57]. Another possibility is dual-loading of drug with a particle-based imaging contrast agent to monitor stent placement procedures.
Tissue Factor Imaging
This technique is a noninvasive molecular imaging tool and can be used to monitor therapeutic delivery. It is based on the fact that biological pathways and metabolic pathways can be activated and visualised before, during, and after delivery of therapeutics. A key factor in the success of this technique is the full understanding of the molecules involved in the pathologies, for example, atherosclerotic plaques and ischaemic myocardium. These molecules could then be targeted, treated, and monitored with dual-loaded therapy. Numerous molecules are expressed in atherosclerotic plaques and activated platelets and can be visualised, for example, nanoparticle targeted fibrin imaging. This is based on the fact that fibrin deposition is one of the earliest signs of atherosclerotic plaque rupture, erosion, and haemorrhage . Following systemic administration the fibrin-specific nanoparticles accumulated at the site of arterial thrombi, which have been visualised by US and MRI [59, 60]. Another application of target particle based tissue factor imaging is that used in monitoring angiogenesis. This is based upon ligand-conjugated paramagnetic nanoparticles, which specifically target αvß3-integrin, a general marker of angiogenesis . This technique has the potential for imaging early events in disease. Combining tissue factor imaging with the transport function of particles should enable us to generate target-specific imaging and shuttle specific therapeutics to the targets of interests. By then applying different imaging modalities, it will be possible to assess the distribution and location of therapeutics and/or particles after their primary target-specific delivery.
This involves the delivery and incorporation of genes at a target site. Currently in vivo transfection and transduction of genes into the vasculature are low . Unfortunately, this technique has been shrouded by concerns regarding the safety and practicality of using recombinant viral vectors in patients and the inefficiency of nonviral transfection techniques . To address this issue, scientists have combined nanotechnology (microbubbles and liposomes) with imaging techniques, such as US, to increase in vivo transfection and the therapeutic expression of genes. The success of liposomal preparations depends on the degree of lipid exchange and thereafter fusion and endocytosis, whereas an emulsion-based approach depends upon the strength of the ligand binding between the microbubble and the cell membrane.
Microbubbles have been used as cavitation nuclei for gene delivery . Once the products reach the desired location, the US beam causes the microbubbles to ossilate, collapse, and thus release their product. The proposed mechanism for their enhanced transfection is not clearly understood but it is likely to be via the process of sonoporation (transient disruption of cell membranes caused by the US beam). This process is likely to be aided by the rapid vibration of the microbubbles at the cell surface and rapid streaming of fluid towards in proximity to the microbubbles. Cavitation also increases capillary permeability, which further augments local access for the released gene product. Experiments have shown that that the blood-brain barrier and vascular endothelial cell barrier can be consistently opened in the proximity of microbubbles by a focused US beam [65, 66]. By using low-frequency US various groups have shown that microbubble based delivery systems improve transfection and transduction [67, 68]. For example, increased gene transfection and transduction has been demonstrated following US-mediated delivery of TIMP-3 plasmid DNA into saphenous vein grafts by increasing their luminal size and preventing their failure .
Once the ligand-conjugated product is released from the microbubble, it acts as a site-specific agent producing high local concentrations, which increase its efficacy. One group has shown that conjugating intracellular adhesion molecules onto echogenic liposomes increased transfection rates and gene expression .
A gene vector that simultaneously expresses a cell surface receptor and a therapeutic protein at the target site and;
A targeted image particle that is overexpressed at the site whose ligands specifically interact with the specific cell surface receptor.
Following expression of both the cell surface receptor and therapeutic protein, it should be possible to localize and assess the function of the gene products.
Endothelial Progenitor Cells
Bone marrow-derived EPC are found in the peripheral circulation . They contribute to re-endothelialisation of damaged vessels, neovascularisation of ischaemic lesions, and play a major role in the pathogenesis of atherosclerosis and cardiovascular disease . They are regulated not only by angiogenic growth factors, cytokines, and chemokines [e.g., VEGF, nitrous oxide (NO)] in response to vascular insult but also by patient lifestyle factors, such as, aerobic exercise, smoking cessation, and medical therapies (statins, rennin-angiotensin system inhibitors, etc.).
A reduction in the circulating number of EPC has been shown to be an independent predictor of mortality and morbidity of cardiovascular disease and is thought to be due to reduced mobilisation from the bone marrow rather than from a reduced number of stem cells . NO bioavailability is influenced by cardiovascular risk factors and may limit EPC mobilisation from bone marrow. Recently, it has been shown that therapeutic transplantation of EPC in patients deemed unfit for any other intervention showed increased collateral vessel formation [73, 74]. Cardiovascular risk factors have been shown to reduce the number and function of EPC with an inverse correlation existing between EPC and number of risk factors . An increasing age and male gender also have been implicated in causing a reduced number and function of EPC [76, 77]. Accumulation of reactive oxygen species secondary to the rennin-angiotensin system in hypertensive patients is one of the strongest risk factors for a reduction in number and function of EPC . Interestingly, the therapeutic advantage of angiotensin II-receptor antagonist (antihypertensive) olmesartan has been shown to increase the number of EPC in normotensive and moderately hypertensive patients . Poorly controlled plasma glucose levels are inversely related to the number of EPC . Insulin resistance is an important factor in endothelial dysfunction and in the progression of atherosclerosis thus therapies to treat type I and II diabetes will be important in the prevention of the disease perhaps via EPC function. Recently, peroxisome proliferators-activated receptor-γ (PPAR-γ) agonists (insulin sensitizors) pioglitazone improved the number and migratory function of EPC in patients with coronary artery disease with type II diabetes . Smoking reduces the number of EPC and quitting restores the level of EPC . Furthermore, the magnitude of EPC restoration was smaller in heavy smokers than light smokers suggesting that smoking causes some permanent effect of EPC . Moderate physical exercise protects against atherosclerosis and it has been postulated that this occurs via increasing NO levels.
Photodynamic Therapy PDT
Photodynamic sensitizors (PDS) are molecules that, following activation by a specific wavelength of light in the presence of molecular oxygen, produce reactive oxygen species. These are cytotoxic and trigger a cascade of biochemical responses that result in cell death. The effect is localised because the light delivery is localised to the desired therapeutic location, thus reducing systemic effects. PDT can be used to destroy cancerous and noncancerous tissues. The first photodynamic sensitizers showed a prolonged photosensitivity and were poorly cleared from the system and lacked long wavelength absorption. Since then, they have become more target-specific (tumour tissue  and subcellular compartments ) and have improved light absorption properties . The benefits of PDT are its ability to destroy targeted cells without destroying normal tissues and that it can be repeated without cumulative toxicity.
There is no doubt to the short-term improvement of angioplasty; however, in the long-term restenosis of lesions impairs the clinical benefit for some patients. The determinates to success include level of vascular remodelling, stimulation of the proliferative, and migratory response of vascular SMC and enhanced production of the extracellular matrix [86, 87]. There also is a complex interaction between neutrophils and platelet activation following balloon angioplasty . Furthermore, macrophages have been shown to activate SMC following vascular injury .
Numerous in vitro studies have shown that PDT can inhibit SMC growth and can decrease experimentally induced intimal hyperplasia. The mechanism by which this occurs is complex and not yet fully understood. PDT causes complete cellular eradication within the vessel wall without an inflammatory or proliferative response, suggesting the mechanism of action may involve changes in the extracellular matrix . Experiments involving PDT in the carotid arteries of rats also have suggested that the mechanism of action is via local inhibition of cytokine release or activation . In vitro PDT has been shown to impair the growth of cultured SMC from atherosclerotic lesions and nonatherosclerotic arteries and, the inhibition of SMCs from atherosclerotic lesions (i.e., activated) was much greater [92, 93]. The changes following PDT may improve the vascular remodelling response and reduce the likelihood of restenosis. Furthermore, the highly cellular environment of a restenotic segment of an atheromatous plaque preferentially takes up drugs, suggesting PDT may have a role both in therapy and prophylaxis of restenosis .
A problem encountered by various authors whilst attempting in vivo studies is that blood impairs the delivery of intravascular light (at 630 nm) . Moreover, there are safety considerations which limit the maximum light dose to prevent spasm, necrosis, and transmural injury . However, atherosclerotic plaque area in hypercholesterolaemic rabbits has been shown to decrease with PDT  and macrophage density in balloon injury models have been observed . Intimal hyperplasia and no thermal injury has been demonstrated in animal models , and in most cases this correlated with histological absence of inflammatory and SMCs in the media. PDT during angioplasty has been shown to produce an acellular media despite regeneration of the intima . Thus, suggesting that it is not necessary to delay PDT after angioplasty to prevent the injury response of restenosis, as PDT at the time abolishes the intimal hyperplasia after the injury. Short- and long-term benefits of PDT have been demonstrated [90, 99].
Photoangioplasty for de novo and restenotic lesions has become possible thanks to newer drugs and safer, less expensive devises. Its potential involves: debulking of atheroma (selective injury and destruction); inhibition of restenosis (via its affects on macrophages, intimal hyperplasia and SMC proliferation); and, the hypothetical “dark” effect of some photosensitisers . Trials have shown in patients with claudication symptoms that PDT is well tolerated and more than 90 % of patients have an US measured improvement in luminal cross-section. These effects were achieved without adverse vascular response or phototoxicity . Endovascular light was delivered by a cylindrical diffuser fibre usually 24 h after systemic Antrin (photosensitiser). The fibre being positioned close to the lesion of interest via a 5–8 French guiding catheter. Light treatment was given for 941 s.
The future of PDT may lie in its ability to prevent the cellular response of restenosis after endovascular procedures. Future investigations will be targeted to determine the synergistic role of photoangioplasty when performed at the same time as therapeutic endovascular procedures. More information is required on safety aspects of the technique and in equipment developments.
The future of IR is bright through development of methods for delivery of nanotechnology, pharmacokinetics, gene therapy, molecular targeting, control of angiogenesis, and other biological processes. With improvements in imaging technology, noninvasive imaging and sophisticated delivery systems IR will continue to be an exciting field, rapidly developing with vast potentials. The development and practice of magnetic resonance-based imaging is likely to become increasingly important and will likely develop as this technique becomes more widely available, accessible, and in line with the development of nonferromagnetic catheters and guidewires. With ever-increasing competition from other specialties development of new techniques and therapies is vital to broaden the horizon of IR and ensure its success in the future. Miniaturization of devices, the development of bioabsorbable stents, and entirely percutaneous treatment of aneurysms are a significant first step.
Conflict of interest
Dr. Charles Ross Tapping and Dr. Mark Bratby have no potential conflicts of interest to declare.