CDU Contributing Editor

ANAHEIM, California – Continued advances in technologies used for the diagnosis and treatment of cardiovascular disease have been a hallmark of the segment for many years, dating to the first open-heart surgery procedure over four decades ago. The annual meeting of the American Heart Association (AHA, Dallas, Texas) remains the largest venue for physicians, scientists, and suppliers in the cardiovascular device market and historically has served as a forum for introduction of the latest technologies. Highlights of this year's AHA Scientific Sessions, held here in early November, included advances in heart assist devices, new developments in the use of biotechnology for surgery, next generation devices for interventional therapy and advances in coronary imaging and monitoring of patients with cardiovascular disease.

New options for heart failure

As shown in Table 1, heart assist devices represent a large and growing market opportunity in the U.S. Considerable attention has been focused on devices such as the AbioCor artificial heart. Although the first patient to receive an implant of the Abiocor device, which is being developed by Abiomed (Danvers, Massachusetts), recently suffered a setback, the company is continuing to pursue its clinical trial program. A total of five patients have now received AbioCor implants, and the first patient has had the device in place for over 130 days. As of mid-November, a total of 273 patient-days had been accumulated with the AbioCor, with no significant problems observed except for the incident with the first patient. All patients who received implants had a 30-day estimated survival of less than 30% prior to receiving their implant.

Another heart assist device discussed at the AHA sessions is the Jarvik 2000 continuous flow pump, a non-pulsatile device developed by Jarvik Heart (New York), a company formed by Howard Jarvik, one of the pioneers in the development of heart assist technologies. The Jarvik device is much simpler and more compact than pulsatile devices, operating at 25,000 rpm to augment blood flow in patients with failing hearts. Studies have shown that the use of completely non-pulsatile flow is problematic for patients who retain their native heart, since the heart degrades if allowed to operate for long periods of time under low mechanical stress. That effect caused problems with early versions of the Jarvik device, including two deaths, since it was initially operated so as to provide essentially all of the pumping action needed by the body. The device is now operated at a lower drive level, allowing the native heart to provide as much pulsatile flow as possible while still providing adequate perfusion for the patient. While the Jarvik 2000 was initially developed for use as a bridge to transplant, Jarvik is now in discussions with the FDA to determine the steps necessary to allow the device to be approved as a destination therapy.

In fact, perhaps the most promising results with heart assist devices are now being achieved with left ventricular assist devices (LVADs). Thoratec (Pleasanton, California) is a leading supplier of LVADs, and is now conducting the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial to determine if its device can also be used as a destination therapy, i.e., not just as a bridge to transplant. Increasingly, bridge to transplant has become a less viable strategy, as the number of patients requiring cardiac support has grown to almost 100,000, while the number of transplants has declined to about 2,600 per year. At a given time, there are about 4,000 patients in the U.S. awaiting transplant. With approximately 4.7 million in the U.S. now suffering from heart failure, and an average half-life of about nine years for heart failure patients, there is a crucial need for therapies other than heart transplant that can improve the quality of life of such patients. More than 3,000 Thoratec Heartmate devices have now been used in patients as a bridge to transplant, with each device costing about $68,000. The REMATCH trial is a Phase III study intended to demonstrate a 33% reduction in mortality for congestive heart failure patients at two years as a result of LVAD treatment. Enrollment in the trial was completed in June 2001, with a total of 129 patients receiving Heartmate implants, and the FDA approved crossover to Heartmate LVAD therapy in August.

So far, results from the REMATCH study have been better than expected, with a 48% reduction in mortality at two years, and 52% survival at one year vs. 25% in controls. The improvement in outcome is four-fold better than the best drug therapy. Thoratec has now submitted a premarket approval application for use of the Heartmate as destination therapy and is also performing a cost-effectiveness analysis. The overall costs for use of the Heartmate as a destination therapy are estimated to be similar to costs for a heart transplant, or about $160,000. The Heartmate will probably be used much like dialysis treatment to support patients with kidney failure, supplementing the heart as needed on a long-term basis.

One possible difference vs. dialysis therapy, however, is that it may be possible for heart function to be restored as a result of LVAD treatment. Studies have shown that some patients' hearts are able to regain part of their pumping ability if supported by an LVAD. Apparently, the heart may be able to regenerate functional tissues, or perhaps restore function to hibernating tissue, if it is not required to bear the full load of supporting the patient's circulation. Furthermore, new approaches using cell implants to restore function in the heart appear increasingly promising, perhaps allowing the unburdened heart to become rejuvenated to a point that would allow removal of the LVAD.

Companies involved in the development of cell transplant therapy for heart failure include Bioheart (Weston, Florida), Diacrin (Boston, Massachusetts), and Geron (Menlo Park, California). In addition, the NOGA mapping device from Cordis/Johnson & Johnson (Miami Lakes, Florida) has been used in a number of studies to guide cell implantation to help ensure proper placement of cells in the target tissue. Successful implants have been performed in damaged hearts using autologous cells cultured from a thigh muscle biopsy. Philippe Menasche, MD, PhD, of Hospital Bichat (Paris) has the longest experience with the technique, having performed the first implant about one year ago. Menasche has used fetal cardiomyocytes as well as bone marrow stem cells for implantation. The key issue encountered with existing approaches is that the growth rate of implanted cells is insufficient to replace the cells lost in most infarcts. Implanted cells have, however, been shown to migrate to areas of ischemia, and some bone marrow stem cells implanted in the heart are able to differentiate to form muscle cells, although there is not definitive proof that they can transform into cardiac myocytes.

The first patient to receive a cell implant in the heart was treated about a year ago, and continues to do well. A total of 10 patients have now received implants in Menasche's lab. Cardiac function has been restored in about 60% of the implanted segments, in areas that were initially akinetic. All patients have shown improved ejection fraction with the average degree of improvement at about 11%. Remaining issues include selection of cell types for expansion, the method of cell delivery, and enhancement of cell survival. Only 1% to 10% of implanted cells survive when implanted in necrotic myocardium (i.e., in the tissue to be rescued), due to a lack of oxygen availability, even though muscle cells are very resistant to ischemia. In addition, patients have experienced arrhythmias after receiving cell implants, but the condition appears to be transient. Menasche is planning to begin Phase II studies in 2002.

An important aspect of the treatment is controlling cell proliferation to avoid cell growth in undesired locations or excessive growth of tissues. Menasche is using a drug manufactured by Ariad Pharmaceuticals (Cambridge, Massachusetts) that alters cell receptor function to allow cell proliferation to be controlled in a reversible manner. Opportunities also exist for devices and media used to culture extracted autologous cells and for devices to deliver cells to the heart. Matrigel, a cell culture medium manufactured by Becton Dickinson Biosciences (Franklin Lakes, New Jersey), is widely used now. For example, it would clearly be preferable to deliver cells via intravascular (transcatheter) means to minimize procedural invasiveness, but at present catheter-based delivery is inferior to a surgical approach using direct injection into the heart. More than twice as many injection cycles can be performed using the surgical technique compared to the transcatheter method. Furthermore, precise localization of the injection is very important, and the orientation of the injection needle can make a substantial difference in success rates. Since survival of implanted cells is highly dependent on the availability of oxygen in the tissues, combining coronary artery bypass surgery with cell transplantation may also help to improve the efficacy of the therapy.

A second approach to using cell transplantation for repair of damaged heart tissue is implantation of pre-formed tissue grafts. Dr. Wolfram Zimmermann of Friedrich-Alexander University (Erlangen, Germany) described a new technique at the AHA sessions that uses engineered heart tissues (EHT), formed by casting cultured cardiac muscle cells in molds to create grafts having the shape needed to repair a damaged region of the heart. At present, the technique has only been assessed in animals, but Zimmerman has demonstrated that such grafts can become vascularized after implantation, and that the cells in the graft express markers and structural characteristics representative of cardiac tissues. However, the animals must be treated with immunosuppressive agents to avoid graft rejection, since non-autologous cells are used, and, at least to date, the researchers have not found that the graft becomes integrated into the heart's electrical network, although the grafts exhibit contractile properties. Advantages of the technique include the ability to create grafts having the desired shapes and sizes to allow repair of all damaged areas, and the ability to create tissues having well-defined contractile properties.

Another important application of tissue engineering in cardiovascular disease therapy is valve repair. As shown in Table 2, the number of valve replacement procedures totaled approximately 80,000 in the U.S. in 1999, and procedure volume has generally been increasing. Tissue engineered valves can potentially offer significant advantages over existing prosthetic or porcine valves in pediatric patients because of the ability of the tissue to grow with the patient, avoiding the need for repeat implant procedures. A variety of approaches are being studied for creating tissue-engineered valves.

As with all clinical applications of tissue engineering, identifying a source of cells for use as a starting material is a significant challenge because of technical, legal and ethical issues. A group led by Kristine Guleserian, MD, of Barnes-Jewish Hospital/Washington University School of Medicine (St. Louis, Missouri) is using endothelial progenitor cells derived from human umbilical cord blood to create heart valves and other structures such as myocardial tissue patches comprised of a bioabsorbable polymer scaffold seeded with cells. The cells are readily obtained from patients undergoing C-sections, and are selected using a CD34 antibody to identify cells of interest. The cells can be cryopreserved, and they are subjected to conditioning by culturing in a pulse duplicator system prior to implantation.

Other researchers developing tissue-engineered heart valves include Simon Hoerstrup, MD, of University Hospital Zurich (Zurich, Switzerland); Pascal Dohmen, MD, of Humboldt University (Berlin, Germany); and Ren-Ke Li, MD, PhD, of the University of Toronto (Toronto, Ontario). Both Hoerstrup and Li are employing a novel approach that involves using mechanical stresses, induced either by stretching or pulsatile flow in the culture medium, to simulate the forces that a native heart valve encounters in vivo. In theory, the approach helps induce tissues to develop so that their characteristics are more like those of native valves in both macroscopic mechanical function as well as at the cellular level. Dohmen is developing both heart valves and bypass grafts using tissue engineering technologies, and has collaborated with Medos AG (Aachen, Germany) in the development of tissue-engineered bypass grafts. The grafts use 4 mm-diameter PTFE prostheses from Medos, coated with glucoprotein to improve cell adhesion, and seeding of autologous, cultured endothelial cells onto the graft in vitro. The grafts are then implanted as an alternative to saphenous vein, internal mammary artery, or other autologous conduits. A total of 21 grafts have now been implanted for a median period of 41 months, and 17 remain patient, considerably more than would be expected for saphenous vein grafts.

Researchers also announced major progress in the use of gene therapy for the treatment of cardiovascular disease at the AHA sessions. A group led by Eberhard Grube, MD, of the Heart Center (Sieburg, Germany), described a trial with a drug under development by Corgentech (Palo Alto, California) known as E2F Decoy. In the PREVENT II trial, a follow-up study based on research originally reported by Zhau and Mann in 1999, E2F is being used to modify the properties of saphenous vein grafts used for coronary bypass to prevent neointimal proliferation and to modify the ability of the grafts to withstand the higher pressure-related stresses experienced in the coronary arteries. According to Grube, the typical rapid deterioration of saphenous vein grafts used as bypass conduits is due in large part to the manipulation of the graft during harvest and implantation, which induces neointimal proliferation after implant. The procedure involves harvest of the graft, followed by placement in a bath containing the E2F agent and application of hydrostatic pressure (0.6 atmospheres) for about 10 minutes, followed by implant of the graft. A 30% reduction in neointimal volume has been achieved, along with a 30% reduction in graft failure. E2F is one of a new class of drugs known as TF decoys. Phase III studies with both coronary and peripheral bypass grafts are now planned.

Promising results also were described by Douglas Losordo, MD, of St. Elizabeth's Medical Center (Boston, Massachusetts), using VEGF-2, an angiogenesis agent from Vascular Genetics (Waltham, Massachusetts). Vascular Genetics is a privately held company funded by investors including Human Genome Sciences (Rockville, Maryland) and Vical (San Diego, California). The studies have also used a catheter, the Myostar, from Johnson & Johnson for use in delivery of VEGF-2 to target tissues. VEGF-2 is an angiogenesis agent used to stimulate growth of new blood vessels in patients suffering from severe angina. In a Phase 1 trial involving 19 patients, a 1.2 point improvement in angina score and improvement in exercise time, as well as improved perfusion scores, were observed in 8 of 12 treated patients. Vascular Genetics is now working with the FDA to complete the design of a multicenter trial.

Revascularization technologies advance

While technologies such as cell transplantation and tissue engineering show promise for use in the future, considerable progress has already occurred in revascularization technology. Minimally invasive cardiac surgery, while not growing as rapidly as was the case only about a year ago, nevertheless remains an important application. New devices just now being widely introduced to facilitate minimally invasive cardiac surgery procedures on the heart include the Symmetry automated anastomosis device from St. Jude Medical (St. Paul, Minnesota); the Axius and the Expose vacuum-assisted positioning devices from Guidant (Indianapolis, Indiana); a new anastomosis clip developed by William Fogarty (the Diamond Clip), a device from HeartStent (Minneapolis, Minnesota); the VCS Clip from Auto Suture (Norwalk, Connecticut); the nitinol U-Clip from Coalescent Technology (Sunnyvale, California); the Solem Graft Connector from Jomed AG (Helsingborg, Sweden); the HeartFlo connector from Abbott/Perclose (Abbott Park, Illinois); J&J's (Warren, New Jersey) Aortic Anastomotic Connector; and the Magnetic Vascular Positioner from Ventrica (Fremont, California). A set of consumable devices for performing minimally invasive coronary artery bypass surgery typically costs about $1,000.

An evaluation of the St. Jude Symmetry connector in humans was described by Thierry Carrel, MD, of University Hospital (Bern, Switzerland). The device uses a stainless steel clip plus a catheter, stent and balloon to perform an anastomosis in about 30 seconds v.s five to eight minutes for a hand-sewn procedure. Carrel has used the Symmetry in 13 patients so far, with generally good results. In particular, use of the device has resulted in shorter on-pump time during bypass surgery procedures. An important development in minimally invasive bypass surgery is the switch from minithoracotomy to sternotomy or ministernotomy. Use of sternotomy allows easier and more complete access to the heart than does the thoracotomy approach and also makes it easier to switch to on-pump support if needed. Furthermore, the post-procedural pain levels are comparable and in some cases less than for minithoracotomy. While procedure volume for minimally invasive coronary artery bypass surgery dropped off for a time after the initial wave of enthusiasm among surgeons, the new techniques coupled with advances in devices are now driving renewed growth in procedure volume.

Drug-eluting stents remain the most significant advance in cardiovascular revascularization technology at present, with restenosis rates for the first group of patients treated with the Cordis Cypher sirolimus-eluting stent still at zero at approximately nine months. The latest data indicates that sirolimus inhibits not only cell proliferation but also the expression of inflammatory cytokines, further reducing the tendency for restenosis to develop. In the larger SIRIUS trial in the U.S., the target vessel revascularization rate remains at zero after 30 days, in a trial in which 550 patients have received Cypher stent implants. However, promising results were also presented at the AHA scientific sessions by researchers evaluating drug-eluting stents from other companies, including Boston Scientific (Natick, Massachusetts) and Cook (Bloomington, Indiana). Studies with the Boston Scientific NIRx paclitaxel-coated stent (the TAXUS 1 study) have shown no restenosis and no thrombosis at six months. The device uses a Pharmalink coating for drug attachment. Studies with Cook's V-Flex Plus coronary stent show a 3% restenosis rate in patients receiving the paclitaxel coated stent vs. 21% in controls. The V-Flex Plus allows the drug to be attached directly to the stent, eliminating the need for a polymer coating. Other studies are in progress with devices from Guidant using the Achieve Actinomycin-D coated stent, and a coated stent from Biocompatibles (Farnham, England).

Another important trial using drug-eluting stents described at the AHA sessions involves the use of the Cordis Cypher stent to treat in-stent restenosis. The ISR (In-Stent Restenosis) study, now under way at Dante Pazzanese Institute of Cardiology (Sao Paulo, Brazil) shows 0% restenosis, 0% target lesion revascularization, no thrombosis and no deaths at four-month follow-up on 25 patients. Those results are an improvement over restenosis rates observed with brachytherapy treatment for in-stent restenosis, the only technology currently approved by the FDA for treatment of the condition. Brachytherapy systems approved for use in the U.S. for the treatment of restenosis include the BetaCath from Novoste (Norcross, Georgia), the Galileo from Guidant and the CheckMate from Cordis.

Coronary imaging, monitoring advances

As therapy for cardiovascular disease continues to evolve toward increased use of less invasive technologies, modalities for disease diagnosis and monitoring of treatment are following a similar trend. Magnetic resonance imaging (MRI) is one of the most promising techniques for use in non-invasive imaging of the coronary arteries, using surface coils for image enhancement as well as, in the future, intravascular imaging devices to allow detailed analysis of internal structures within arteries including vulnerable plaques. MRI is particularly valuable for that purpose because of its sensitivity to the composition of tissues, allowing assessment of changes in plaque composition over time.

However, processing times to render MR images remains too long for routine use, particularly if the modality is used alone. Many researchers are now assessing the possibility of combining ultrafast CT scans with MRI. Ultrafast CT can allow physicians to scan a large region of the coronary vasculature to identify areas where a lesion may exist, and then to follow up with MRI at the identified sites to obtain a detailed characterization of the degree of blockage as well as plaque characteristics. Only a handful of institutions in the U.S. now have both ultrafast CT and MR angiography systems in place to allow such procedures to be performed. But the trend is definitely toward increased resolution and reduced processing time, and it is likely that there will be continued progress in the field, according to suppliers. The first clinical applications for MR cardiac imaging will probably be for perfusion imaging. Leading suppliers in the field include GE Medical Systems (Waukesha, Wisconsin), Magna Lab (Lynnfield, Massachusetts); Surgi-Vision (Gaithersburg, Maryland); and Siemens Medical Solutions (Iselin, New Jersey). GE has a marketing agreement with Surgi-Vision, a supplier of high-resolution MR imaging coils, including intravascular devices, and also recently announced an agreement to acquire Imatron (South San Francisco, California), the supplier of the C300 Electron Beam Computed Tomography (EBCT) system. Imatron has achieved rapid growth in market penetration recently, climbing from worldwide product sales in 1995 to $53.3 million last year, a compounded annual rate of more than 32% over that period. The noninvasive nature of the technology, which allows detection of coronary calcium deposits to indicate regions of plaque build-up, has been an important factor in its acceptance, along with the speed of analysis and the ability of the technology to detect a wide range of disorders. The Imatron system sells for about $2.2 million.

Another advance in imaging of vulnerable plaque involves the use of super paramagnetic iron oxide (SPIO) particles as a contrast agent. SPIO particles, when given intravenously, are taken up by macrophages, a cell type that typically appears in elevated numbers in vulnerable plaque. Clinical trials are now under way to assess the utility of SPIO particles in noninvasive detection of vulnerable plaques. An SPIO-based contrast agent, Endorem, is available from Guerbet (Paris).

Other new techniques described at the AHA sessions for vulnerable plaque detection include a system for analysis of biological markers that has been developed to a prototype stage by Bio-Profile Catheter Systems; a Raman spectroscopy device that provides chemical fingerprints of plaque, under study by a group led by Sweder Van de Poll at the Leiden University Medical Center (Leiden, the Netherlands); and an optical coherence tomography system that can image the vessel wall with a resolution of 2 microns to 10 microns, under development by a group led by Dr. Gary Tearney at Massachusetts General Hospital (Boston, Massachusetts).

Cardio-Optics (Boulder, Colorado) is developing another new technology for catheter-based imaging of coronary vessels. The company's Trans-Blood Visualization (TBV) system uses near infrared imaging through a fiber optic catheter to allow direct viewing of structures within an artery to a depth of one centimeter. The device is being evaluated for imaging of vulnerable plaque, and for use in guiding pacemaker lead placement. It can also be used in conjunction with ablative technologies. The company started animal studies with the TBV system in October.