CDU Contributing Writer

NEW ORLEANS, Louisiana – The market for products used to treat cardiovascular disease continues to be one of the most dynamic segments of the medical device industry, and one that offers significant potential for investment returns and new technology-based ventures. The 73rd annual scientific sessions of the American Heart Association (AHA; Dallas, Texas), held here in mid-November, addressed a number of emerging technologies that are expected to play a major role in the market in the future. Among the technologies highlighted at the conference were new developments in the emerging field of tissue engineering with applications in cardiovascular therapy; genomics technology that will provide more powerful approaches to diagnosis as well as new, more effective drug therapies; and new techniques for the treatment of heart failure, one of the most prevalent types of cardiovascular disease and perhaps the most challenging issue facing cardiovascular specialists today.

Physicians and researchers described a wide variety of new developments, including the first-ever application of cell transplantation therapy for cardiovascular disease. While the results of that study are highly promising, such treatments will likely take years to implement, and in the interim a number of other innovative approaches may prove important as well as commercially attractive. The widespread applications of genomics are continuing to impact cardiovascular disease management, by both improving the ability to diagnose patients at an early stage as well as helping to identify targets for drug development. Less-invasive treatments for cardiovascular disease continue to advance in the marketplace, increasing the number of patients who are candidates for treatment and helping to lower morbidity in patients who undergo procedures such as revascularization and repair of valve defects. Finally, rapid progress continues in percutaneous interventional technologies, threatening to make surgical treatment obsolete.

As shown in Table 1, the rate of growth of percutaneous interventional procedures such as coronary angioplasty and stenting has exhibited minimal evidence of slowing, while the number of coronary artery bypass procedures, at least in the U.S., has shown signs of reaching a plateau and of entering a declining phase. Breakthrough technologies such as brachytherapy and coated coronary stents may eventually eliminate the problem of restenosis, further increasing the attractiveness of interventional therapy compared to surgery. However, even if such innovations are successful, there will continue to be millions of individuals in the U.S. with cardiovascular conditions that require treatment, since in many cases interventional treatment, while it has made major advances, will only serve to delay, and not eliminate, mortality from cardiovascular disease.

Tissue engineering milestone reported

A major advance announced at the AHA gathering was the first successful application of tissue engineering technology for the treatment of heart failure. As described by Phillipe Menasche, MD, of Hopital Bichat (Paris), a Phase I human trial was initiated with the implantation of cultured cells into the heart of a 72-year-old patient. The patient had suffered a previous myocardial infarction, leading to heart failure with an ejection fraction of 20%, and was not a candidate for percutaneous revascularization. Treatment involved implantation of a large number of myoblasts derived from a biopsy of the patient's own thigh muscle. After biopsy, the cells were cultured in large numbers in a highly controlled environment that met the requirements for biological therapeutic products as defined by the FDA, and were purified by repeat passages to obtain approximately 800 million cells, 65% of which were myoblasts or progenitor muscle cells. The patient was then treated both with coronary artery bypass grafting as well as implantation of the cells in 33 sites in and around the region of infarction and necrosis.

At five months after the procedure, the patient's ejection fraction had increased to more than 30%, and the disease classification improved from New York Heart Association Class III to Class I. Furthermore, no arrhythmias were observed. The latter point is quite significant, since most heart failure patients die from arrhythmias. The investigators observed evidence of tissue remodeling and also saw restoration of metabolic activity in tissues that were previously shown to be nonviable. While the results of the study clearly represent an important milestone for both heart failure treatment and tissue engineering technology, the short period of follow-up, as well as the confounding effect of the CABG procedure performed at the same time as the cell implant, make it difficult to draw any definitive conclusions regarding efficacy from the study. Nevertheless, the experiment provides initial support for the safety of tissue engineering therapy for cardiovascular applications. The group led by Menasche is planning to continue the studies and move forward with a Phase II trial.

A number of other groups are pursuing additional applications of tissue engineering. As shown in Table 2, the potential market for tissue-engineered products used in cardiovascular therapy is estimated at $7.3 billion in the U.S. alone based on year 2000 estimates of disease prevalence and related therapeutic procedures, including $5.3 billion for cell transplantation products to treat heart failure, $215 million for tissue-engineered heart valves and $1.6 billion for tissue-engineered vascular bypass grafts. A leading company pursuing the development of cell transplantation therapy to treat heart failure is Osiris Therapeutics (Baltimore, Maryland). Osiris has developed and patented mesenchymal stem cell (MSC) technology, which involves isolation of autologous cells from a patient's bone marrow. The company has not yet progressed to human studies, but in animal experiments the Osiris MSCs have been shown to proliferate and produce remodeling (thickening) of the heart tissue in heart failure models, whereas controls exhibit progressive thinning of the same region of the heart. Although the treatment did not confer a survival advantage on the animals, a relatively small number of cells were implanted and follow-up is only up to eight weeks.

Another company pursing the development of cell transplantation therapy for myocardial tissue regeneration is Diacrin (Cambridge, Massachusetts). Diacrin recently received investigative new drug clearance for a six-patient Phase I clinical trial of heart muscle regeneration using autologous cell implants.

So far, cell transplantation for heart failure has been performed using direct injection with a small (typically 30-gauge) needle. Transcaheter delivery, a more desirable alternative, has not yet been demonstrated in human studies. The delivery technique for cell implantation therapy in heart failure is likely to be critical, since studies by Menache and others have shown that cell survival following implant, as well as differentiation into cardiac muscle cells, is highly dependent on the region of the heart into which the cells are deposited. Cells implanted into the interior of non-viable scar tissue do not proliferate, whereas cells implanted in viable tissue or in the border between normal and scar tissue grow and differentiate. Other groups, including one led by Ray Chiu, MD, PhD, of McGill University Health Centre (Montreal, Quebec, Canada), and another led by Terrence Yau, MD, of Toronto General Hospital (Toronto, Ontario, Canada), have also studied the use of stem cell implants to treat heart failure and observed similar differentiation patterns. According to Antonio Beltrami of the New York Medical College (Valhalla, New York), who presented a poster on myocyte regeneration in the post-infarcted human heart at the AHA sessions, the preferential regeneration of myocytes at the borders of an infarction may be due, at least in part, to higher levels of IGF-1 growth factor in those regions.

One of the newer companies in the tissue engineering field, and one that is specifically focusing on heart muscle regeneration, is Bioheart (Weston, Florida). Bioheart was founded in June 1999 by Robert Lashinski and Howard Leonhardt, also the founder of World Medical, a company that developed an endovascular graft for aneurysm treatment and was sold to Arterial Vascular Engineering for $62 million in 1998, and subsequently became part of the Medtronic AVE (Santa Rosa, California) unit of Medtronic (Minneapolis, Minneapolis). Bioheart has licensed a number of patents pertaining to the use of tissue engineering and cell transplantation and has developed technology for the endovascular delivery of cells derived from thigh muscle and bone marrow using a catheter with a slidable injection needle. The company has retained a number of leading physicians and scientists in the tissue engineering and vascular therapy areas, and it completed an $8 million private placement in August. Researchers working with Bioheart include Ray Chiu, MD; Doris Taylor, PhD; and Menasche.

Tissue engineering also is being applied to the development of heart valves. A group led by John Mayer, MD, at Boston Children's Hospital (Boston, Massachusetts) has pioneered that application. An important application for tissue-engineered valve technology is the treatment of valve diseases in pediatric patients. Existing prosthetic valves have the disadvantage of not growing with the patient, and they must be replaced as the child ages. For a variety of reasons, bioprosthetic valves are limited to use mainly in patients over 60 years of age. Mayer's team had previously demonstrated that valve structures can be engineered by creating a polyglycolic acid (PGA) scaffold in the desired shape for the valve and then seeding the scaffold with cells derived from the patient and cultured in vitro. After implantation, the scaffold gradually degrades and is replaced with a structure regenerated by the patient's own system.

Metabolix (Cambridge, Massachusetts) has supplied many of the biomaterials used in Mayer's studies. The latest advance is the use of a new PGA/poly-4-hydroxybutyrate scaffold, a thermoplastic material that is amenable to manufacture by conventional molding methods, and the development of a bioreactor that is used to provide conditions that signal the cells to grow in a tailored manner as they are cultured in-vitro. The bioreactor technique allows the cells to develop optimal properties similar to those of a mature valve leaflet, including the ability to withstand the mechanical stresses encountered in vivo.

Another group developing tissue-engineered heart valves, led by Michael Sacks, MD, of Pittsburgh, Pennsylvania, described a sophisticated approach to tissue engineering that allows complex, multi-layered structures to be developed. The structures mimic those observed in native valve leaflets, which have highly anisotropic mechanical properties. The structures consist of modified PGA scaffolds coated with extracellular matrix. So far, the valves have not been assessed in animal studies. LifeCell (The Woodlands, Texas) and Advanced Tissue Sciences (La Jolla, California) also are developing tissue-engineered heart valves.

Another application of tissue engineering in the treatment of cardiovascular disease is the synthesis of vascular bypass grafts. Existing synthetic grafts are only suitable for peripheral bypass because of problems with thrombosis in small-diameter devices. As a result, surgeons must use autologous vessels, usually saphenous veins derived from the patient, for coronary bypass. However, up to 20% of patients have too few or no autologous saphenous vessels available for harvest, and the harvesting procedure itself results in significant morbidity. Tissue-engineered grafts could potentially offer an alternative. Thoratec (Pleasanton, California), which recently announced a proposed merger with Thermo Cardiosystems (Woburn, Massachusetts), is among the companies developing advanced synthetic grafts. Companies developing tissue-engineered grafts are listed in Table 3.

Studies of tissue engineering for vasculogenesis were described at the AHA conference by Jeffrey Isner, MD, of Brigham & Women's Hospital (Boston, Massachusetts). Isner's approach involves harvesting of immature endothelial cells from the patient, culturing the cells in the presence of vascular endothelial growth factor (VEGF) and then re-implanting the cultured cells into the tissues surrounding the heart to promote formation of new vessels. The approach differs from previous experiments that involved injection of VEGF itself or the VEGF gene into patients in the hope of promoting blood vessel growth or angiogenesis. Those studies have so far been disappointing, although recent results from the VIVA trial, described by Timothy Henry, MD, of Hennepin County Medical Center (Minneapolis, Minnesota), with VEGF treatment indicate that growth factor or growth factor gene therapy may continue to hold some promise.

The development of tissue-engineered vascular grafts remains at a very early stage, and none of the groups working in the field are yet in clinical trials. New synthetic grafts are likely to enter the market before tissue-engineered devices, in part because the regulatory approval process for a tissue-engineered device is likely to be more involved. And so far, it is not clear that tissue engineering would offer a significant benefit over advanced synthetic materials, particularly since the use of autologous cells will require a biopsy and a lengthy cell culture procedure before the bypass could be performed. An important advantage of synthetic grafts is their ready availability, which greatly shortens procedure time and could be of significant benefit in emergency situations.

The time frame for introduction of any tissue-engineered product for treating cardiovascular disease is likely to be at least five years. While some tissue-engineered products for treatment of burns, ulcers and other skin conditions already are on the market (sales of tissue engineered medical products of all types were approximately $65 million worldwide in 1999), the field is pushing the envelope of existing knowledge about cell growth and function. For cardiovascular applications, a significant amount of research and development will be needed before safe and useful products can be introduced. Nevertheless, tissue engineering using cell implants may prove to be a more viable approach to revascularization than angiogenesis using gene therapy or growth factors, since tissue engineering uses existing cells rather than attempting to induce coronary cells to transform and create new blood vessels in vivo.

Increased investment in heart failure segment

While the treatment of heart failure represents a major opportunity for the development of tissue engineering products, many other new technologies are being evaluated for treating the 5 million patients in the U.S. with that disease. Two new mechanical devices for treating heart failure were described at AHA. One, the Cardiac Support Device (CSD), under development by Acorn Cardiovascular (St. Paul, Minnesota), seeks to reverse the progressive dilation of the heart that distorts cardiac myocytes, leading to hypertrophy and myocardial dysfunction. The CSD is a semi-elastic polyester web pouch that is placed over the heart as part of an open-heart surgical procedure. According to researchers who have used the CSD, it could potentially be placed during a beating-heart procedure. The device applies a continuous force to compress the heart back toward its normal size. In animal studies, the CSD has been shown to reduce cardiac hypertrophy. More importantly, indicators of cardiovascular function such as ejection fraction, as well as levels of molecules such as phospholambans and cell stretch proteins, revert toward normal over time after application of the device. The CSD produces an initial 6% to 7% reduction in size, which apparently is sufficient to start the cascade of events that reverses the degradation in function associated with heart failure.

The Acorn device, while applying the force needed to correct cardiac hypertrophy, does not completely constrict the heart, allowing it to pump additional blood during exercise. Human studies with the Acorn CSD have been conducted by Wolfgang Konertz, MD, of the Unfallkrankenhause (Berlin, Germany) insurance fund, on 11 patients so far with congestive heart failure. All of the patients were good candidates for heart transplant, and all were also being treated with the most recently recommended drugs at optimal dose levels, including ACE inhibitors, beta blockers and digoxin. At 12.2 month follow-up, there were no device-related adverse events, and only one death due to heart failure. Ejection fraction improved from 21% to 32% at six months, and the average NYHA Class rating for the treated patients improved from 2.5 to 1.8. A worldwide randomized trial using the CSD is now under way.

Drug therapy for heart failure also is continuing to advance. ACE inhibitors and beta blockers have been shown to provide clear benefit, in an additive manner, for heart failure. Most recently, Valsartan, a drug from Novartis Pharmaceuticals (East Hanover, New Jersey), has been shown to provide benefits including reduced morbidity for patients who were already being treated with either ACE inhibitors or beta blockers, but not both. Valsartan reduced combined all-cause mortality and morbidity by 13.3% and allowed a 27% reduction in hospitalizations as compared to patients not receiving the drug. However, combined treatment with ACE inhibitors, beta blockers and Valsartan produced a slightly worse outcome as compared to treatment with ACE inhibitors and beta blockers only, prompting researchers to recommend that physicians use caution in prescribing all three drugs at once.

Yet another important development in heart failure treatment is the use of remote monitoring technology to track patients at home with heart failure. Numerous companies – including Alere Medical (San Francisco, California), American TeleCare (Eden Prairie, Minnesota), Nexan (Alpharetta, Georgia), AvidCare (Milwaukee, Wisconsin), CYBeR- CARE (Boynton Beach, Florida), and Hom MED (Brookfield, Wisconsin – have introduced systems that allow physicians to remotely monitor their heart failure patients at home, in real time in some cases. The Nexan NX-300 system is one of the newest to be described, and uses a disposable sensor for continuous monitoring of 2- or 3-lead ECG, respiration, and oxygen saturation, plus point-in-time measurement of blood pressure, lung function and weight. Patients also can record events as they occur, e.g., to capture an ECG trace during an arrhythmia. The Nexi sensor can transmit via the Personal Data Assistant (PDA) portable wireless module to a base station in the patient's home or other alternate site setting, up to a range of 15 meters, and the base station is connected via modem to a receiving station in the physician's office. Applications for the system include monitoring of heart failure patients, including titration of drug therapy and diagnosis of sleep apnea. The system will either be sold outright or leased for between $150 and $200 per month. Investors in the company include Quintiles Transnational (Durham, North Carolina).

Another supplier in this segment is I-Trax.com (Philadelphia, Pennsylvania). I-Trax.com has adapted an online database originally developed for military applications to the health care market, and has developed a patient portal that connects to specialists such as cardiologists. The I-Trax.com database is intended to serve as a data warehouse that can be accessed by physicians, patients, health care providers and public agencies. Another supplier of online systems, iMedica (Mountain View, California), has developed a service that provides prescription ordering, recording of patient symptoms and parameters, and consult letters online. The system uses the Fujitsu Lifebook or Slate computer as an interface device, vs. the palm computers used by other companies such as ParkStone (Weston, Florida), AllScripts (Libertyville, Illinois), PocketScript (Mason, Ohio), iScribe (Redwood City, California), MedicaLogic/ MedScape (Hillsboro, Oregon), and ePhysician (Mountain View, California). iMedica said it believes the Fujitsu machines are easier to use and provide the computing power that is needed for most physicians' office applications. The company allows physicians to connect to a network of 33,000 pharmacies nationwide for prescription placement.

Genomics in heart disease

Another major topic at this year's AHA conference was the role of genomics in heart disease. As shown in Table 4, a number of genes have already been identified that are implicated in heart disease, and studies are already in progress to assess the potential to use some of those markers in patient management. The thromobospondins represent a particularly important set of candidate genes with possible applications in prevention of early death from myocardial infarction. As described by Eric Topol, MD, of the Cleveland Clinic Foundation (Cleveland, Ohio), during a press conference at the AHA meeting, presence of thrombospondin 1, 2 or 4 results in a 2-, 4-, or 10-fold increase in risk of myocardial infarction before age 40 in men and before age 45 in women. The risk appears to be isolated to individuals of Caucasian descent. Thrombospondins are responsible for cell adhesion, and low levels predispose an individual to inflammation. There is a 25% prevalence of the suspect genes in the Caucasian population.

Another important application of genomics in cardiovascular disease management is pharmacogenomics, involving the use of genetic tests to predict a patient's response to drug treatment, or to assess the need for prophylactic drug therapy in individuals at risk for various syndromes. For example, genetic tests for Factor V Leiden are already available that can help predict if a patient is prone to thrombosis, allowing physicians to possibly prevent a heart attack or stroke by implementing aggressive anticoagulation therapy in at-risk patients who are undergoing surgical procedures that predispose them to thrombosis.

Pharmacogenomics also can potentially help to avoid adverse drug reactions by identifying those patients who are genetically predisposed to an adverse event because of their genetic makeup. While the market opportunity for such tests is substantial, there are a number of barriers to adoption that are likely to slow the rate of market development. Confidentiality issues have caused some physicians to avoid the use of genetic testing, and such issues would become important in screening healthy individuals for disease predisposition. In addition, test turnaround times are at present probably too long to make routine use practical. However, the pharmaceutical industry is already embracing pharmacogenetics testing both to improve the clinical trial process and to enhance the efficiency of drug development programs.

Experts predict that all physicians eventually will use pharmacogenetic testing to guide drug therapy. Three tiers of testing applications are likely to develop. The first would include general or family practice physicians, who would use the tests along with broad genetics knowledge to make referral decisions. A second tier would include specialists having highly specific knowledge of genes related to various cardiovascular diseases and of the treatments for those diseases. Finally, a third tier will include geneticists who will provide specialized consultations for other physicians who are managing patients with rare genetic conditions.

However, the key question regarding the implementation of pharmacogenomics and genetic testing for cardiovascular disease is the time frame for clinical use of the technology. While the human genome has been sequenced, recent studies of hypertension, for example, have failed to show a relationship of genotype with disease. As discussed by Gordon Williams, MD, of Brigham & Women's Hospital (Boston, Massachusetts) at AHA, most diseases are the result of multiple genetic defects on a population level, even though for individual patients a single defect, perhaps coupled with environmental factors, can be identified as the causal agents. So far, most studies of the role of single gene variations in causing cardiovascular disease, such as genetic causes of predisposition to arterial thrombosis, have been negative.

The development of clinically useful genomic tests will consequently require multifactorial studies of large patient populations in order to achieve the level of sensitivity and specificity available in existing non-genomic tests. Such studies are likely to require many years to complete, leading to a long time frame for widespread implementation of pharmacogenomic testing. However, there are certainly a number of disorders related to single-gene defects, including certain types of hemophilia, some coagulation disorders, TPMT gene defects causing adverse drug reactions, and her-2/neu amplification in breast cancer. Tests and related pharmaceuticals for those diseases will enter the market sooner and represent an opportunity for suppliers to capture leadership positions in the market in its early stages.

Companies that are actively involved in research to study genetic factors in cardiovascular disease include Amgen (Thousand Oaks, California) and Targeted Genetics (Seattle, Washington), both studying genetic approaches to the management of hemophilia.