(Circulation. 1997;95:773-776.)
© 1997 American Heart Association, Inc.
Articles |
Second International Symposium on Cardiovascular Drug Delivery
the Harvard-MIT Division of Health Sciences and Technology, Cambridge, and the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Frederick G.P. Welt, MD, Massachusetts Institute of Technology, 77 Massachusetts Ave, Room 56-341c, Cambridge, MA 02139.
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Introduction |
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 Top Introduction Vasculoproliferative DiseasesVasculothrombotic DiseasesMyocardial DiseasesValvular and Electric DiseasesRegulatory Issues |
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The Second Annual International Symposium on Cardiovascular Drug Delivery was held October 13-15, 1996, in Cambridge, Mass. Drs Steven Bailey of the University of Texas, Elazer R. Edelman of the Brigham and Women's Hospital, Harvard Medical School and MIT, and Keith March of the University of Indiana and the Krannert Institute organized the 2½-day event. More than 225 people attended, and 47 speakers from a range of cardiovascular disciplines presented overviews of principles and leading experiments in the field.
The symposium commenced with seven interactive workshops dedicated to critical issues in cardiovascular drug delivery. Dr Keith Robinson of Emory University and Dr Robert Schwartz of the Mayo Clinic reviewed the current state of animal models of cardiovascular disease and the techniques available for their quantitative assessment. An extensive and comprehensive review of model protocols and tissue preservation, handling, and analysis was provided, along with an evaluation of computer-based resources for morphometric assessment. Drs Renu Virmani and Andrew Farb of the Armed Forces Institute of Pathology provided an overview of cardiovascular pathology and anatomy including a detailed histological account of accelerated vascular disease in animal models and humans. Dr Jeffrey Hubbel of the California Institute of Technology and Dr Prasad Shastri of MIT described the field of polymer chemistry and biomaterials. Starting with first principles, they provided rules by which to choose proper materials for drug-delivery platforms and tissue-engineered scaffoldings. Dr Charles Lambert of the University of Florida and Dr Bailey discussed the current status of catheters and their use in local vascular drug delivery. They reviewed the currently available catheters as well as considerations of basic design, functional characteristics, and results from animal and human studies. Dr Steve Hanson of Emory University and Mark Lovich of MIT described issues related to pharmacokinetics and how this discipline impacts on drug delivery and biological understanding of vascular disease. Dr Matthew Nugent of Boston University and Keith March provided an overview of molecular biology fundamentals and techniques relevant to cardiovascular biology. Finally, Dr Ron Waksman of the Washington Hospital Center and Dr Judah Weinberger of Columbia University reviewed the science and status of radiation therapy. The remainder of the symposium was devoted to didactic sessions with specific presentations in five general areas (the four basic diseases of the heart and blood vessels that include vasculoproliferative diseases, vasculothrombotic disease, diseases of the myocardium, and congestive heart failure; and valvular heart disease) and a final session devoted to regulatory issues.
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Vasculoproliferative Diseases |
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The first session of the meeting was devoted to vasculoproliferative diseases and was chaired by Drs Peter Libby and Victor Dzau of the Harvard Medical School and the Brigham and Women's Hospital. They noted that more than 1 000 000 people each year suffer from obstructive arterial disease complicated by myocardial infarction, cerebrovascular accidents, and peripheral disease and gangrene. Dr Libby led the session, noting common themes in the accelerated arteriopathies of angioplasty restenosis, endovascular implant failure, bypass graft loss, and transplant rejection and provided a discussion of the progress and perils of gene transfer and local drug delivery in the treatment of these lesions. He raised questions regarding the sufficiency of current understanding of the fundamental processes governing the choice of target genes. He asked that one consider carefully whether smooth muscle cell proliferation itself is the appropriate target given the relatively slow rate of proliferation of these cells, the possible role they play as the "guardian" of the fibrous cap, and the contributions of other extracellular elements in the restenotic lesion. In addition, Dr Libby raised the as-yet-unresolved issues of the efficiency of gene transfer, the appropriate dosage and timing of delivery, the most effective means of delivery, and the possible inflammatory role of viral vectors.
Dr Dzau spoke next about genetic engineering, focusing on the exciting work involving antisense oligodeoxynucleotides to cell-cycle regulatory genes such as PCNA and CDC2 kinase in a model of graft restenosis. In a rabbit model in which jugular veins were grafted onto carotid arteries, the preoperative treatment of veins with these oligodeoxynucleotides shifted wall thickening from neointimal hyperplasia to medial hypertrophy and provided resistance to diet-induced atherosclerosis.
Dr Eric Allaire from the Hopital Mondor in Creteil, France, followed with discussion of a novel approach to prevention of aneurysm enlargement and rupture. Smooth muscle cells were transfected with TIMP-1, an inhibitor of matrix metalloproteases, and introduced into decellularized and engrafted rat abdominal aortas. Transfected cells showed sustained expression of TIMP-1 and prevented enlargement and rupture of the grafts. Dr Edelman next reviewed the history of local vascular drug delivery, using heparin as an example and extending from the earliest experiments involving systemic administration to perivascular and periadventitial implants and finally to the cell-based delivery of heparan sulfate and similar compounds.
Dr Warren Zapol of the Massachusetts General Hospital extended the discussion of local drug delivery to include his work with inhaled nitric oxide in the treatment of pulmonary hypertension associated with various disease states such as chronic pulmonary hypertension, adult respiratory disease syndrome, pneumonia, and congenital heart disease as well as after cardiopulmonary bypass. He emphasized the local nature of the action of inhaled nitric oxide due to its short half-life and the avoidance of side effects such as hypotension that have been associated with systemic therapies in the past.
The second session continued the discussion of vasculoproliferative diseases and was chaired by Dr Ulrich Sigwart of the Royal Brompton National Heart and Lung Hospitals and Dr Paul Didisheim of the National Heart, Lung, and Blood Institute. Dr Sigwart discussed stent-based therapies, including issues of stent design, anticoagulation, and subacute thrombosis, and the possibilities of polymer-coated stents as drug-delivery devices. In addition, he raised the question of whether there will be a role for stent-based local drug delivery given the superior performance of stents with respect to restenosis.
Dr Ezra Deutsch of Temple University discussed the use of catheter-based drug delivery, focusing on his work delivering low-molecular-weight heparin as a bolus at the time of PTCA. He has shown this modality to cause less restenosis in the rabbit iliac artery model, and in explanted coronary artery segments, he documented the effective delivery of catheter-based material (horseradish peroxidase). Interestingly, drug was deposited preferentially along fracture planes.
Dr Jean-Francois Tanguay of the Montreal Heart Institute discussed the local pharmacotherapy of heparin after PTCA and stenting, including both its anticoagulant and antiproliferative characteristics. He detailed the promising results of pilot human studies and the ongoing LIHPS and HIPS trials, which will examine local heparin delivery before stenting.
Dr Robert Schwartz of the Mayo Clinic then discussed energy therapies as local pharmacotherapy, emphasizing the role of factors other than simple endothelial denudation alone for generation of neointimal hyperplasia. Using examples of animal models in which heat and UV light injured the vessel wall, leading to medial necrosis and abundant neointimal hyperplasia, he reasoned that the media could not be the sole source of neointima. He argued that alternatively, the media may be actively inhibiting neointimal hyperplasia through an as-yet-unknown mediator.
Last, Edoardo Camenzind of the Thorax Center in The Netherlands provided a detailed and comprehensive review of the current ongoing clinical trials involving local pharmacotherapy.
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Vasculothrombotic Diseases |
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The next session was chaired by Dr Ian Sarembock of the University of Virginia Health Science Center and Dr James Willerson of the University of Texas Medical School at Houston and dealt with vasculothrombotic diseases. The discussion was led by Dr Robert Rosenberg of Harvard Medical School, Beth Israel Hospital, and MIT, who spoke about his murine model involving thrombomodulin gene knockout and its application to human arterial thrombosis. He emphasized the lethality of the homozygous mouse and the need to superimpose an environmental factor (hypoxia) in the heterozygous mouse to create fibrin deposition. He also discussed the efforts of his laboratory to produce mice with focal reductions in thrombomodulin associated with site-specific increases in fibrin deposition and neointimal hyperplasia, suggesting that there may be regional differences in the properties of endothelium. In addition, he discussed his work with point mutations to create a viable homozygote with <1% thrombomodulin.
Dr Michael Sefton of the University of Toronto next discussed his work with heparin-immobilized catheters using heparin–polyvinyl alcohol hydrogel. He illustrated the point that although the catheters are effective in keeping thrombin production low, they have had the unexpected result of activating platelets that in the long run may be more deleterious to patients and thus require additional study.
Dr Michael Ezekowitz of Yale University School of Medicine and Dr Anthony Gershlick of the University of Leicester discussed their interesting collaboration involving targeted thrombolysis. A conjugate of urokinase and a glycoprotein IIb/IIIa antibody was linked to an antibody directed against damaged endothelium and evaluated in a rabbit iliac artery model of angioplasty. Systemic administration of the conjugate reduced both platelet deposition and neointimal hyperplasia. When a glycoprotein IIb/IIIa antibody was immobilized to cellulose-coated stents expanded within a deep-injury rabbit iliac artery model, arterial occlusion rates were significantly reduced although neointimal hyperplasia was not affected at 28 days.
Dr Willerson discussed the vascular biology of endothelial and medial vascular injury and described a unique attempt to identify unstable plaques using the temperature differences associated with mononuclear cell accumulation. Atherosclerotic plaques from carotid endarterectomy specimens were probed for temperature variation immediately on explantation and then fixed and examined histologically. Areas of increased temperature were found to correlate positively with an increased number of monocytes and inversely with fibrous cap thickness. Additional studies with infrared imaging to detect temperature variability within the plaque are promising. Dr Willerson also discussed his work with adenovirus-mediated transfer of the cyclooxygenase gene to injured porcine carotid arteries, in which decreased rates of thrombosis were achieved.
The last talk of the session was given by Dr Stefan Janssens of the University of Leuven, Belgium, who concentrated on studies involving the gene transfer of a constitutively active endothelial nitric oxide synthase using the novel Infiltrator catheter. This catheter has longitudinal strips that penetrate the internal elastic lamina on low-pressure inflation. In a porcine coronary artery model, preliminary studies show a trend toward decreased neointimal hyperplasia in the treated animals.
The last session of the first day was also devoted to vasculothrombotic disorders and was chaired by Dr S. Ward Casscells of the University of Texas–Houston Medical School and Neil Eigler, MD, of the UCLA School of Medicine. Dr Howard Greisler of the Loyola University Medical Center discussed molecular and pharmacological strategies to induce endothelialization of vascular grafts. To this end, Dr Greisler and his colleagues studied grafts pretreated with FGF-1 and heparin in a canine aortoiliac model and showed decreased platelet deposition and complete endothelialization at 28 days and abundant neovascularization of the graft interstices. Low doses of heparin in association with FGF-1 stimulated smooth muscle cell proliferation in contrast to higher doses of heparin, which inhibited cell proliferation. These data may have significant importance in smaller grafts.
Dr Campbell Rogers of Harvard Medical School and Brigham and Women's Hospital described the current status of drug-eluting stents. He reviewed the biological targets such devices might have on the basis of the fundamentals of the biological response, which involves stent thrombosis, inflammation, and intimal thickening. The importance of the stent platform itself, including responses to metal and polymer components, was reviewed. Finally, the importance of pharmacokinetics and deposition of stent-released drugs was discussed briefly. Dr Richard Stack of Duke University followed this discussion with a review of the potential of stents as drug-delivery devices. He discussed the issues of stent design and polymer-coating biocompatibility as well as the choice of drug to be delivered. He focused attention on the glycoprotein IIb/IIIa receptor antagonists and nitric oxide formulations as the most promising drugs on the horizon.
The last talk of the day was given by Dr Bailey, who discussed clinical trials in progress in local vascular drug delivery. He cited the technological advances enabling local or regional drug delivery but also noted that the large number of trials stemmed in part from the lack of any one technology to dominate all others. He also emphasized that delivery efficiency is still limited by catheter development. Finally, he noted that virtually all of the studies dealt with conventional agents such as heparin, low-molecular-weight heparin, or urokinase and that continued drug discovery and catheter development would enhance further trials.
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Myocardial Diseases |
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TopIntroductionVasculoproliferative DiseasesVasculothrombotic DiseasesMyocardial DiseasesValvular and Electric DiseasesRegulatory Issues |
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The following day began with a session concerned with local drug delivery as it pertains to myocardial diseases and was chaired by Dr March and Dr Jeffrey Isner of Tufts Medical School and St Elizabeth's Hospital. Dr Michael Simons of Harvard Medical School and Beth Israel Hospital led the discussion with a review of angiogenic factor release in the treatment of the ischemic myocardium. Dr Simons focused on his work with local perivascular administration of bFGF in a porcine coronary artery model in which ischemia was produced through the use of ameroid constrictors and bFGF was delivered via the placement of heparin-alginate microspheres. He observed none of the toxicological or acute hemodynamic side effects that had plagued earlier attempts with systemic administration of bFGF. Local bFGF treatment increased coronary artery flow, angiographic patency, myocardial contractility, and microvascular reactivity to ADP. Dr Isner extended the discussion of angiogenesis to include the treatment of peripheral vascular disease and the use of active release from plasmid-transfected cells. On the basis of the promising results of studies in the hindlimb of rabbits treated with local VEGF that showed increased angiogenesis and increased flow, Dr Isner described the early results of the arterial gene transfer of VEGF via a hydrogel-coated balloon in a patient with an ischemic limb. Digital subtraction angiography demonstrated increased collateral flow at both 4 and 12 weeks after treatment. Interestingly, spider angioma developed on the treated leg; through biopsy, these revealed proliferating endothelium. Dr Isner also discussed the potential of VEGF therapy in the treatment of restenosis by promoting reendothelialization of the injured artery.
Dr Dan Burkhoff of the Columbia Presbyterian Medical Center discussed laser therapy of the ischemic myocardium, emphasizing the need to understand the different pathological changes associated with injury from different types of laser therapy. He discussed the preliminary yet positive results of laser therapy in patients with angina who are unsuitable for coronary artery bypass grafting. Both animal studies as well as human autopsy reports challenge the hypothesis that laser channels maintain their patency in the long term, suggesting that clinical improvement may be through a different mechanism. Histological examination of hearts at autopsy, as well as PCNA staining and BrDu uptake in animal models, suggest that this alternative mechanism might involve neovascularization in response to the injured myocardium.
Dr March next presented the novel concept of pericardial delivery of genetic and pharmacological agents using a hollow, helix-tipped catheter positioned transmurally across the ventricular wall. He described studies involving the intrapericardial delivery of the nitric oxide donor diazenium-conjugated albumin before coronary balloon overstretch injury in the porcine model. Histomorphometry revealed significant reductions in both neointimal area and adventitial area.
Dr Frank Giordano of the University of California at San Diego discussed therapeutic cardiovascular gene transfer concentrating on modalities of gene transfer as well as potential applications, including the use of calcium regulatory genes in the treatment of heart failure, the use of heat shock proteins as myocardial protective agents, and finally, the use of growth factors to promote angiogenesis in the ischemic myocardium.
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Valvular and Electric Diseases |
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TopIntroductionVasculoproliferative DiseasesVasculothrombotic DiseasesMyocardial DiseasesValvular and Electric DiseasesRegulatory Issues |
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Local cardiovascular drug delivery is not restricted to vascular restenosis alone, and attention was directed toward the role it might play in valvular and electric diseases of the heart in the next session chaired by Dr Robert Levy of the University of Michigan Medical School and Dr Frederick Schoen of Harvard Medical School and Brigham and Women's Hospital. Drs Schoen and Levy spoke in succession about the issues of calcification in prosthetic valves and efforts to ameliorate this process through local drug delivery. They discussed the prevention of calcification through tissue modification with detergents and bisphonates, the inhibition of calcification with Al2+ or Fe3+ pretreatments, and novel design concepts to reduce cuspal stresses and subsequent calcification.
Dr Vinod Labhasetwar of the University of Michigan discussed the application of local drug-delivery techniques in the therapy of arrhythmias. Dr Labhasetwar discussed the use of transvenous defibrillator catheters as well as pacing electrodes to deliver antiarrhythmic agents such as lidocaine, sotalol, ibutelide, and propanolol. With the use of ibutelide in conjunction with implantable defibrillators, Dr Labhasetwar described both a decrease in the number of cardiac events as well as a decrease in threshold. One of the novel features of these devices is the use of iontophoretic implants that can release drugs in a reliable and titratable manner through the use of an applied electric current.
Last, Ken Stokes of Medtronic Inc discussed the history of the development of pacemaker drug-eluting electrodes, emphasizing the work done with the application of dexamethasone ester to electrodes, which has much reduced the complication of threshold exit block due to inflammation.
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Regulatory Issues |
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TopIntroductionVasculoproliferative DiseasesVasculothrombotic DiseasesMyocardial DiseasesValvular and Electric DiseasesRegulatory Issues |
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The last session of the conference was devoted to regulatory issues concerning new devices and was chaired by Dr Martin Leon of Washington Hospital Center and Dr Michael Rosenblatt of Harvard Medical School, MIT, and Beth Israel Hospital. Dr Leon discussed the history of the regulatory process involved in the evaluation of new devices. He described the shift during the last two decades from open-registry clinical trials of the 1980s that emphasized patient safety, with minimal interaction between the FDA and industry, to the mandated clinical trials of the 1990s with growing emphasis on efficacy and increasing FDA-industry interaction, to the present requirement for demonstrated superiority of outcome rather than simple efficacy. Although he is encouraged about the increased dialogue between the FDA and industry, he expressed concern regarding the rigid regulatory climate that is driving industry to perform trials abroad. Dr Leon then posed several questions to the committee including: (1) Are animal investigations necessary, and if so, what information is critical? (2) Should animal trials demonstrate clinical efficacy? (3) Are drug-device systems always evaluated as a whole, or is it possible to evaluate some components separately? (4) What clinical trials are necessary to ensure patient safety?
Dr Bram Zuckerman of the Device Section of the FDA then spoke regarding the FDA's role in the regulation of devices. He outlined the process necessary to bring a device to market and emphasized the FDA's mission to bring safe and effective products to the market in a timely fashion. In addition, he stated that the critical issues for FDA approval of devices are (1) the emphasis of clinical utility over cosmetic utility, (2) adequate preclinical testing, (3) appropriate clinical trial design with emphasis on randomized trials over those with historical controls, and (4) appropriate labeling of devices. Veronica Price of the Device Section of the FDA and Dr Norman Stockbridge of the Drugs Section of the FDA then spoke about some of the specifics of the approval process for drug-device combinations. A general discussion between session speakers and symposium attendees ensued, with several important points being made. It was repeatedly emphasized that early communication with the FDA was both welcome and would streamline and shorten the approval process. Questions were raised about the possibility of using surrogate end points rather than hard clinical end points (such as mortality) given the relatively small but real differences between devices.
Following in the vein of increasing communication between the different partners in the device design and approval process, Dr Rosenblatt addressed the changing relationship between academy and industry. He discussed the lengthy process between discovery of a drug and market introduction and the enormous odds against a given drug making it through all the hurdles to market. He also documented the increasing financial role of industry in drug research and the shrinking role of academia and raised questions about how this would affect the training of researchers in the future, suggesting that industry may have to take on a larger role in this process. After this, Anthony Gershlick of the University of Leicester, England, gave a comprehensive report of the working group on clinical trials in Europe. Last, Nicolas Chronos of the Emory University School of Medicine called for a worldwide web page devoted to the issue of new devices, emphasizing participation from academia, industry, and the FDA to disseminate information, encourage participation in clinical trials, and make results of these trials known to the community quickly.
The meeting was an acknowledged success, broaching issues in a unique forum. Next year the symposium will be merged with the annual Transcatheter Cardiovascular Therapeutics course (TCT-IX). TCT-IX and the Third International Symposium on Cardiovascular Drug Delivery will therefore be held cojointly at the Washington Convention Center September 24-28, 1997.
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Selected Abbreviations and Acronyms |
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