CDU Contributing Editor

ORLANDO, Florida The 2003 meeting of the American Heart Association (AHA, Dallas, Texas), held here in early November, provided a window on the most recent developments in the diagnosis and treatment of heart disease, and on key new technologies that are expected to drive market trends in the future. Cell transplant therapy was one of the technologies highlighted at the conference, with a considerable expansion evident in the number of research programs directed at using cell therapy to treat heart failure and coronary artery disease.

Heart failure treatment also represents a growing opportunity for suppliers of left-ventricular assist devices, total artificial hearts, and heart repair technologies. Another tactic to address the growing problem of heart failure is the use of rapid cooling of the heart tissue of myocardial infarction patients, to help prevent the deterioration of tissue function that leads to heart failure. Advances in surgical repair and revascularization techniques that promise to provide less invasive treatment of coronary artery disease also were described at the conference, and that may offer a means to treat patients with severe disease who have no other treatment options.

Noninvasive technologies for the diagnosis and monitoring of cardiovascular disease also were highlighted at AHA, including new ultrasound modalities and new technologies that combine ECG analysis with monitoring of heart sounds to speed the treatment of myocardial infarction patients in the emergency department. Technologies for noninvasive monitoring of cardiac output and blood pressure are also finding increased acceptance in the cardiovascular device market, as the use of monitoring outside of the traditional hospital setting expands.

Advances in cell implant therapy

The use of cell implantation to treat heart disease, including applications to restore cardiac function in patients with heart failure as well as revascularization techniques employing cells to stimulate the growth of new blood vessels in the heart, has been an expanding area of research since initial successes were reported by Philippe Menasche, MD, at the Hopital Europeen Georges Pompidou (Paris) about two years ago. A number of studies have been reported within the past year that indicate such therapies are effective using both stem cells from a variety of sources as well as skeletal muscle cells, as were used in the initial studies conducted by Menasche.

The mechanisms that are responsible for improvement in cardiovascular function are not yet well characterized. In the case of revascularization, one advantage of cell therapies as compared to traditional surgical or interventional techniques is that the latter are not capable of reaching vessels of less than 1.5 mm in diameter. Cell treatments, on the other hand, may allow generation of new blood vessels to provide blood flow to additional regions of the heart. Implanted stem cells can potentially act by a number of mechanisms, including differentiation into specialized cells such as myocardial striated muscle cells to improve contractile function of the heart, differentiation into vascular endothelial cells to increase tissue vascularization, or fusing with resident myocardial cells to improve their function.

A key factor in the success of cell transplant therapy is the delivery method used to implant cells in the heart. One widely used technique is electromagnetic guidance, a method that uses the NOGA catheter from Cordis Endovascular (Miami Lakes, Florida). The NOGA catheter can be used to map electrical activity in the heart to determine which regions require treatment and to help guide placement of an infusion catheter. Some researchers have also used direct injection of cells into the myocardium, as well as non-targeted intracoronary infusion of cells.

One of the most promising studies reported at the AHA sessions was conducted by Emerson Perin, MD, PhD, of Baylor College of Medicine (Houston, Texas), using stem cells isolated from the bone marrow of patients with severe ischemic heart failure. The study was the first to be conducted in a group of patients with severe disease, which included five patients who had qualified for heart transplant therapy. Mononuclear cells were isolated from bone marrow and injected through a catheter into heart muscle tissue using NOGA guidance. Objective improvements in patient status were observed at follow-up, including a 19% to 24% increase in oxygen consumption, and the improvement in all five of the transplant patients was sufficient to result in their removal from the transplant waiting list. On average, the treated patients exhibited a greater than one stage improvement in New York Heart Association (NYHA) class at four months. The researchers are now preparing to start a large-scale randomized controlled trial of the therapy.

In addition to the use of devices such as the NOGA catheter for guidance of cell implantation, opportunities may also exist for device suppliers in the cell isolation process. For example, some researchers are using the CS3000 system from Baxter International (Deerfield, Illinois) to isolate cells from bone marrow for subsequent implant. Opportunities may also exist for improved catheters used to inject cells, since existing catheters have efficiency for delivery of viable cells of only about 30%.

Some researchers are evaluating intracoronary infusion of bone marrow cells or of stem cells isolated from peripheral blood for heart failure treatment. In the TOPCARE-CHF study, a team led by Birgit Assmus, MD, of Frankfurt, Germany, is using a technique that involves isolation of circulating progenitor cells from 250 ml of peripheral blood or isolation of bone marrow cells, cultivation for three days and intracoronary infusion of the expanded cell preparation via catheter. The procedure has proven to be safe, and there is evidence of an improvement in NYHA class and in regional contractility, with large-scale clinical trials now in the planning stage.

A Phase I study of autologous myoblast transplantation in patients with ischemic cardiomyopathy was conducted by Nabil Dib at the Arizona Heart Institute (Phoenix, Arizona) using a cell therapy system developed by GenVec (Gaithersburg, Maryland). The study involved a group of 27 patients, including 21 who had coronary artery bypass graft surgery and six who had LVAD implants along with the cell treatment. The GenVec procedure involves isolation of cells from a thigh muscle biopsy, culture over a period of four to six weeks at the GenVec facility in fetal bovine serum, and return of the cells for injection into the patient. The extended culture procedure provides a large number of cells for injection, allowing each patient to receive 10 to 15 injections containing 10 million cells each. At 18.5 months' follow-up, there was evidence of engraftment of cells in the heart, including the formation of myotubes. The engrafted tissue also exhibited angiogenesis capability. The study was designed to demonstrate the safety of the technique, and no arrhythmias or other adverse events were reported, although one patient received an ICD implant. In addition, improvement in cardiac function based on ultrasound imaging was observed in the CABG group. The ability to implant large numbers of cells is likely to prove important in achieving a significant improvement in patients in subsequent studies since only about 4% of the implanted cells survive based on studies conducted by other researchers.

Another strategy is to use drugs such as granulocyte macrophage colony stimulating factor (GMCSF) along with chemokine injection to help stimulate growth of cells in the bone marrow and their migration to the heart to produce new blood vessels. Joseph Woo of the University of Pennsylvania (Philadelphia, Pennsylvania) reported on the use of GMCSF in conjunction with delivery of an endothelial progenitor cell chemokine, stromal cell derived factor (SDF), to stimulate the growth of new blood vessels. In animal studies, growth of new blood vessels expressing endothelial cell markers were observed in the heart following subcutaneous injection of GMCSF and intramyocardial injection of SDF. In addition, the animals exhibited increased blood pressure, enhanced cardiac ejection fraction, improved cardiac output, increased heart contractility, and improved ventricular function vs. controls that had also been subjected to a ligation procedure to induce heart failure. Although the research is at an early stage, Woo said he believes that the new vessels are formed from cells originating in the bone marrow and subsequently directed to the heart by the chemokine. Such an approach avoids the need for isolation and injection of autologous bone marrow cells, instead stimulating and directing the process of cell proliferation within the patient to promote angiogenesis in infarcted tissues. Other researchers, such as Menasche, have used fibroblast growth factor as a stimulant to enhance the survival of transplanted cells.

A group led by Helmut Drexler, MD, at Hannover Medical School (Hannover, Germany), has evaluated cell transplant therapy in heart failure patients who had a recent myocardial infarction. A controlled study involving 60 patients was conducted, with 30 patients receiving transplants of autologous bone marrow cells. The treated group had a 6.7% increase in ejection fraction vs. a 0.7% increase in controls, a highly statistically significant difference. Furthermore, no increase in arrhythmias was observed in the treated group vs. controls at six months post-transplant. The cells were isolated from the patients at four to five days after their heart attack, purified and infused the same day.

If cell transplant therapy proves to be safe and effective, it could offer a considerably more cost-effective approach to treating heart failure than existing methods that provide electrical or mechanical assistance to the heart using implantable devices. The cost of autologous cell transplant therapy is estimated at between $8,000 and $15,000 by physicians participating in current clinical studies, including about $5,000 for the catheterization procedure, a few thousand for cell processing and additional costs related to hospitalization. That compares to costs per patient ranging from $35,000 to $300,000 per patient for other heart failure treatments, as shown in Table 1. Cell transplant therapy would potentially be applicable to a larger number of patients than device therapy, due in part to its low cost but also because it promises to be useful in patients with mild disease, to help prevent further deterioration, as well as in severe disease, as demonstrated by the studies conducted by Baylor's Perin.

Nevertheless, device-based treatments are available now using technologies that have FDA approval, and there is clear evidence that such therapies provide substantial benefits. Left ventricular assist devices, such as the HeartMate from Thoratec (Pleasanton, California) and the Novacor LVAS from WorldHeart (Ottawa, Ontario), are available in the U.S. for the treatment of advanced heart failure, and the DeBakey VAD from MicroMed Technology (Houston, Texas) and the LionHeart LVAS from Arrow International (Reading, Pennsylvania) are now available in Europe. As discussed by Soon Park, MD, of the University of Minnesota (Minneapolis, Minnesota) at the AHA sessions, the Heartmate device has been shown to provide life-saving therapy for myocardial infarction patients in cardiogenic shock, allowing 78% of such patients to survive up to three years vs. a very dismal prognosis for untreated patients. Thoratec's sales of cardiovascular products, primarily the HeartMate, almost doubled between 2000 and 2002, exceeding $84 million worldwide for fiscal 2002.

John Boehmer, MD, of the Penn State College of Medicine (Hershey, Pennsylvania), described a European study using the Arrow LionHeart in which 26 patients with low ejection fraction have been enrolled. The Clinical Utility Baseline Study (CUBS) has evaluated survival at two years, as well as adverse device-related events. More than two-thirds of the enrolled patients survived, and a low rate of infections was observed, consistent with the design of the Arrow device that employs transcutaneous transmission of the electrical energy used to drive the pump, thus avoiding the need for transcutaneous leads that can serve as a route for infection.

Another therapy that is showing increasing promise is surgical ventricular restoration, or SVR, using the CorRestore System manufactured by Somanetics (Troy, Michigan). The CorRestore System consists of a bovine pericardial implant that is used as part of a surgical procedure to restore the ventricle to a normal, undilated shape, improving the pumping efficiency of the heart and reducing the strain on the heart that results in cardiomyopathy. In a study involving 74 patients, including 62% in Class IV heart failure, 23% received an implant of the CorRestore patch. Seventy-three percent of the treated patients survived at five years, and improvement was observed in ejection fraction. The CorRestore System has been on the market for about two years, with sales of less than $1 million in 2002.

Another emerging therapy for improving outcome in patients with myocardial infarction is tissue cooling. Studies have demonstrated that cooling of infarcted myocardial tissue until blood flow is restored can have beneficial effects on cell survival, reducing the loss of viable myocardium and minimizing the degradation in heart muscle function that typically accompanies a major heart attack. A variety of technologies are under development, including the Artic Sun system from Medivance (Louisville, Colorado), the Allon 2001 System from MTRE Advanced Technologies Ltd. (Or Akiva, Israel), the Cool Suit from Life Recovery Systems (Alexandria, Louisiana) and the CoolGuard 3000 from Alsius (Irvine, California). Researchers also have evaluated techniques such as delivery of a microparticle ice slurry through a feeding tube for rapid cooling of MI patients in emergency situations. The goal of rapid cooling therapy is typically to produce a 3 C decrease in body core temperature as rapidly as possible. Mild hypothermia is thought to suppress many of the chemical reactions associated with injury in ischemic tissues. It cannot be applied indiscriminately, however, since there is a risk of adverse effects, including arrhythmias, infection, and blood clots.

The MTRE whole-body cooling system is one device that has been cleared for marketing in the U.S. for use in tissue cooling therapy, and consists of a control console priced at $14,750 and a disposable garment priced at $295 for general cooling or warming applications and a second version for bypass surgery applications priced at $80 to $100. According to MTRE, patients can derive some benefit from tissue cooling therapy within a six-hour window following onset of ischemia. The MTRE system can provide a drop in pulmonary artery temperature of greater than 5 C in about 20 minutes. The Medivance system is priced at $30,000, and includes a disposable component priced at about $1,000. It can provide a 4 C reduction in core temperature in one to two hours. Other systems, such as the Alsius Cool Guard, use catheter techniques to achieve very rapid cooling, but require an invasive procedure for catheter placement, increasing the time required for setup. The optimum method for hypothermia therapy, which may depend on patient management logistics, remains to be determined. But an advisory statement from the International Liaison Committee on Resuscitation and the AHA recommends use of the technique on unconscious adult patients who still have spontaneous circulation after cardiac arrest.

New coronary revascularization technologies

Although the treatment of heart failure represents a major emerging market opportunity, the existing cardiovascular device market is dominated by products used in coronary revascularization, including coronary stents and products used in coronary artery bypass graft surgery. As shown in Table 2 below, the number of coronary artery bypass graft procedures is declining as a result of continued advances in percutaneous intervention using coronary stents and the strong preference of patients for less-invasive therapy. Nevertheless, well over 500,000 coronary artery bypass graft procedures are performed annually worldwide, and the number of procedures is expected to remain at that level for most of the decade. One important trend in surgical bypass therapy is the development of less invasive surgical techniques, including off-pump surgery, which has helped to make surgical bypass more attractive to patients by reducing post-procedural morbidity and recovery time. According to leading suppliers of less-invasive coronary artery bypass surgery products, minimally invasive procedures now comprise 35% to 40% of all CABG procedures performed in the U.S. In part, the increase in utilization of minimally invasive techniques is attributable to improved device technologies that have allowed better access to the heart while minimizing the adverse effects on hemodynamics associated with heart manipulation. Previously, surgeons were limited mainly to performing LIMA-LAD bypass due to the complexity of maintaining adequate blood flow to the heart when performing procedures requiring multiple bypass grafts, making minimally invasive bypass surgery applicable to only about 15% of all CABG patients. Now, with improved devices for maintaining heart position during surgery, the number of candidate patients has expanded. Experts expect that penetration will increase to 65% to 70% within the next few years.

More advanced technologies now under development are expected to drive additional expansion in the number of patients who can be treated with surgical bypass. Some of the most promising new technologies are described in Table 3. For example, Percardia (Merrimack, New Hampshire) is developing the VSTENT, a device that can be implanted using percutaneous techniques to perform a ventricle-to-vein bypass (VPASS). The technique relies on arterial retroperfusion, a technique that was first tried experimentally in 1948 but that resulted in serious complications due to insufficient drainage of the coronary vein. The VSTENT avoids such complications by use of a pressure-regulating feature in the device design, and provides a new treatment option for patients who lack suitable autologous blood vessels that can be used for conventional bypass grafts, or who have complex disease that is difficult to treat with multiple grafts. The VSTENT is comprised of a balloon expandable metallic stent covered with an ePTFE membrane and a heparin coating. As discussed by Peter Boekstegers of Grosshadern Hospital (Munich, Germany) at the AHA sessions, results of the ADVANTAGE study using the device in 28 patients produced generally positive results, although occlusions of the stent occurred in some patients.

Another device that shows promise for improving the ability to perform less invasive coronary bypass surgery is the MVP system from Ventrica (Fremont, California). The MVP is a magnetic vascular coupling system used to perform anastomosis in bypass surgery and was developed primarily for use in minimally invasive procedures where hand-sewn anastomoses are difficult to perform. At the AHA sessions, Uwe Klima, MD, of Hannover Medical School, described a clinical evaluation of the MVP in 10 patients. The device uses magnets that are placed in the graft as well as in the vessel following cutdown. The anastomosis is then completed simply by approximation of the two magnets. The magnets are shaped so that there also is a mechanical locking feature that ensures proper positioning once they are in contact. The total anastomosis time averaged 146 seconds, with 53 seconds required to insert the magnets. Total procedure time was two hours. There were no complications related to the MVP system, but one patient suffered an infection of the skin incision. At six months, a 100% patency rate was observed for the grafts. Similar results have been obtained in other studies using the device in the U.S. and Europe. In a prior study performed with the device on saphenous vein grafts, patency was 85% at two years, which compares favorably to experience with hand-sewn anastomoses. The MVP System is applicable to vessels ranging from 1.5 mm to 4.0 mm in diameter. Animal studies have indicated that the magnets do not cause safety issues when performing magnetic resonance imaging (MRI) at a few weeks post-implant, but Ventrica recommends that MRI not be performed until six months after implant. The primary limitation of the MVP device noted by Klima is that it is difficult to use for arteries having a thick wall of more than 0.5 mm. That accounts for only about 1%-2% of all cases, however. The Ventrica device is now available for clinical use in Europe, and launch in the U.S. is targeted for April 2004, according to Klima.

An update on progress with a new tissue-engineered vascular graft for use in coronary artery bypass graft surgery was provided by Todd McAllister of Cytograft Tissue Engineering (Novato, California). The Cytograft technology uses endothelial cells and fibroblasts isolated from a patient's superficial vein, and then cultured in vitro for three to four months. Fibroblasts are initially cultured around a cylindrical mandrel to form the outer wall of the graft, and endothelial cells are then cultured on the interior lumen to form a two-ply structure consisting of autologous cells and resembling a native artery. The burst pressure of the graft is midway between that of saphenous vein and native artery, and a mechanical pre-conditioning process is performed as part of the graft fabrication to produce good compliance. The most recent studies have involved implantation in immune deficient rats. Inspection of some of the grafts at six months revealed a clean inner lumen and an intact vessel wall, and the cells forming the graft were found to be viable. A subsequent study in primates with a tissue-engineered abdominal aortic graft showed 100% patency at up to eight weeks in three animals. There was some evidence of graft dilation initially after implant, but the condition resolved and was no longer evident at eight weeks. Cytograft has demonstrated that the grafts have a shelf life after fabrication of up to nine months. The primary application for tissue-engineered grafts is in the surgical treatment of patients who lack suitable autologous blood vessels for use in bypass. However, such grafts would also eliminate the need for harvesting of autologous arteries or veins, significantly reducing the invasiveness and morbidity of bypass surgery.

Noninvasive monitoring in heart disease

The trend toward use of less-invasive treatment of heart disease is being mirrored by the growing adoption of noninvasive technology for diagnosis and monitoring. One example is the rapid growth in use of noninvasive cardiac output monitoring. In a session at the AHA meeting moderated by Jan Headley of Instrumentarium (Helsinki, Finland), a number of noninvasive and minimally invasive cardiac output monitoring technologies were evaluated, including noninvasive monitors such as the BioZ ICG Monitor from CardioDynamics (San Diego, California) and the Iq monitor from Wantagh (Bristol, Pennsylvania); transesophageal echo systems, including the CardioQ from Deltex Medical Group plc (Chichester, UK) and the Hemosonic from Arrow International; gas exchange monitors from Novametrix/ Respironics (Murrysville, Pennsylvania), the SensorMedics unit of ViaSys Healthcare (Conshohocken, Pennsylvania) and Datex Ohmeda, a unit of Instrumentarium; and pulse contour monitors from LidCo Ltd. (Cambridge, UK) and Pulsion Medical Systems AG (Munich, Germany).

The BioZ and IQ monitors both employ impedance cardiography and are the only completely noninvasive monitors available, according to Headley. An evaluation of the CardioDynamics BioZ found acceptable correlation with invasive thermodilution measurements, with correlation coefficients ranging from 0.71 to 0.93 in a number of studies. The Iq system exhibited a lower degree of correlation, and was not considered to be accurate for use in critically ill patients. The CardioDynamics system is achieving increased market penetration, with sales likely to reach $30 million in 2003, up from $23.5 million in 2002.

The company estimates the potential market for its products at $5 billion worldwide ($800 million in recurring revenue), including $2.7 billion in the hospital segment and $2.3 billion in the non-hospital segment. Market penetration is estimated at 1.5% in the physician's office market and less than 1% in the hospital market. The company now has more than 2,300 customers and expects to exceed 1 million monitoring procedures this year. CardioDynamics is continuing to focus on the non-hospital market for now but will begin to increase its marketing efforts in the hospital segment in 2004. A study to be published in 2004, ED-Impact, will show a 24% change in treatment patterns as a result of use of the system, and there are now six separate indications for use that are reimbursed under Medicare.

Inovise Medical (Newberg, Oregon) introduced the Audicor system, a new product for use in the diagnosis of myocardial infarction and heart failure. The Audicore system uses correlated audioelectric cardiography (COR) technology, which combines ECG and heart sound analysis to provide improved diagnosis of heart conditions without interfering with conventional 12-lead ECG measurements. The $4,995 system uses two sensors priced at $20 each that are connected into the ECG lead assembly via adapters and provides both ECG and sound traces along with a detailed report that gives an estimate of the location and size of a myocardial infarct. Studies performed with the Audicor system demonstrated a 32% to 76% greater sensitivity for MI detection than conventional ECG algorithms. The company is focusing on applications in the emergency department and chest pain clinic, and has implemented efforts to obtain Medicare coverage for use in the physicians' office setting.

Ultrasound imaging is another noninvasive diagnostic technology that is attracting increased attention in the cardiology device sector. A new segment has emerged for portable or hand-held ultrasound systems capable of performing cardiology analysis, led by suppliers such as SonoSite (Bothell, Washington) with its 5-pound Elite system. As shown in Table 4, the U.S. market for hand-held ultrasound systems is estimated at more than $100 million for 2003, with growth forecast to exceed 30% annually over the next five years. Other suppliers have entered the market for general-purpose portable ultrasound products, and GE Medical Systems (Waukesha, Wisconsin) plans to introduce a new compact system for cardiology that will provide image quality similar to that available with its VIVID 4.

Other competitors in the general-purpose portable ultrasound products segment include Philips Medical Systems (Andover, Massachusetts), Biosound Esaote (Indianapolis, Indiana), Medison (Seoul, South Korea) and Terason (Burlington, Massachusetts).

A new capability demonstrated at the AHA sessions by GE Medical is tissue synchronization imaging, implemented in the VIVID 4, which provides a simplified approach to interpreting quantitative strain image data using color-coding and has important applications in the diagnosis of NYHA Class III and IV patients.