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Transforming standards of care in congenital heart defects
by Leo A. Bockeria, MD
Congenital heart defects are the most common type of birth defect in the United States and are the leading cause of birth defect-associated infant illness and death. It has been estimated that in the United States alone, congenital heart defects affect nearly 1% of births per year, and about 1 million American adults are living with a congenital heart defect.
Although the majority of minor forms of congenital heart defects, such as tiny atrial or ventricular septal defects and small patent ductus arteriosus, do not require urgent specialized cardiologic care, infants with complex so-called critical congenital heart diseases require complex surgical procedures over a period of many years.
Under current standards of care, surgeons may implant a graft to repair the damaged or malformed heart and blood vessels, most commonly with synthetic non-absorbable polymer (eg, expanded polytetrafluoroethylene), autologous tissues (such as pericardium and saphenous vein), allografts and xenografts. Unfortunately, such materials have been linked to structural deterioration, thrombogenicity and increased susceptibility to infection, thus necessitating lifelong anticoagulant therapy and antibiotic prophylaxis. Additionally, current graft materials do not have the ability to grow with the patient, which is particularly important for pediatric patients to avoid repeated operations during development.
Consequently, interest is growing in the use of tissue-engineered grafts, which can grow and remodel, thus helping to eliminate the need for repeated surgical procedures.
Advances in supramolecular technology
One approach under development for the treatment of congenital heart malformations is the use of biodegradable matrices that stimulate and guide the body’s natural healing response. Other approaches being investigated include the use of pluripotent or multipotent stem cells.
Xeltis has developed a new therapeutic category called endogenous tissue growth (ETG), which stimulates tissue repair without the need for stem cells, growth factors or the introduction of animal-based grafts. The technology used as the basis for the self-healing implant technology is based on the work of Jean-Marie Lehn, PhD, co-winner of the 1987 Nobel Prize in chemistry for work in supramolecular chemistry.
The ETG technology utilizes a synthetic biodegradable polymer that was developed using nanotechnology and comprises electrospun nanofibers to create a porous matrix. The matrix is flexible and strong enough to handle the dynamic loads of the CV system and creates the optimal porous environment necessary for cell penetration and subsequent tissue growth.
With ETG technology, surgeons can use unique implants designed to allow the body to repair itself by growing natural, healthy tissue. Because the tissue produced through ETG is the patient’s own, this treatment has the potential to overcome the limitations of current standard of care such as rejection or tissue calcification.
Early clinical experience
The biomechanical characteristics of the ETG conduit have been assessed in vitro, and the safety and hemodynamic properties of the conduit demonstrated in pig hearts. Currently, the ETG implant is being evaluated in a first in-human feasibility study to address the treatment of univentricular disorders in children, at the Bakoulev Center for Cardiovascular Surgery in Moscow. The first patient was implanted with the ETG conduit in October. As of February, five patients aged 4 to 12 years had received treatment with implant. In this study, each patient undergoes a physical examination, ECG and echography every 3 months for up to 1 year. At the 6-month follow-up, MRI examination will also be performed to evaluate the function of conduit.
Although it is too early to discuss the patients’ long-term prognoses, initial outcomes look promising. Since these patients had congenital cyanotic heart disease, one of the most obvious changes after treatment was that the skin color changed from a blue tone to pink, indicative of improved blood flow to the lungs, and thus increased oxygen content in arterial blood. Moreover, the first patient to undergo treatment with the ETG implant is now doing remarkably well and is already enjoying an improved quality of life. She is also able to do more of the activities other healthy children her age are able to do.
Clearly, longer follow-up is needed to fully assess the efficacy of the ETG implant; however, it may be possible for these children to be treated with only one surgery in their lifetimes.
The procedure
The surgical procedure used to implant the device is similar to that of the modified Fontan procedure (extracardiac total cavopulmonary connection), a common palliative surgical treatment used in children with univentricular heart defects. The suturing is also similar to that used in “traditional” heart surgery. Consequently, cardiothoracic surgeons will not require extensive training to be able to use this novel technology.
The procedure itself is quite straightforward. First, it is necessary to cut off the supply of blood through the inferior vena cava, as is the case, for example, in a heart transplant procedure. The right atrium is then closed, and the inferior vena cava anastomosed to one end of the conduit. Once this is achieved, the opposite end of the conduit is then connected to the right pulmonary artery.
It is important to select the right patients for this technology. Specifically, patients should be aged at least 4 years; have sinus rhythm with a normal-sized right atrium; no anomalous drainage of system (cavae) veins; mean pulmonary BP ≤15 mm Hg; and a pulmonary vascular resistance of <4 Wood units. Additionally, the diameter of the pulmonary artery and aorta should be close or equal to 0.75, the ejection fraction should exceed 60% and patients must have a competent atrioventricular valve; patients who have acquired negative effects from previous operations may not be suitable candidates for the ETG conduit. Additionally, it is also essential to be aware of the potential for bleeding after surgery and take appropriate steps to prevent this. Before surgery with the ETG implant was performed, there were some concerns regarding the incidence and extent of bleeding that might occur; no postsurgical bleeding or additional suturing has yet been observed.
Future potential
The first commercial product to incorporate ETG technology is a replacement pulmonary valve designed to address life-threatening congenital heart malformations in children. This “self-healing” proprietary biodegradable polymer also has the potential to change the practice of cardiac and vascular surgeries, which hundreds of thousands of patients undergo every year. According to the pioneers of the technology, Lehn and Bert Meijers, PhD, it could potentially be used in other areas of CV surgery and may have applications outside cardiology. However, although its principle will be applicable to a wide number of medical conditions, the mechanical properties of the matrix will have to be adapted according to each scenario. Further, clinical experience/outcomes thus far suggest that this novel technology, ultimately, has the potential to improve cardiac and vascular surgical procedures and could even lead to a fundamental shift in the treatment of congenital heart diseases.
For more information:
CDC. Congenital Heart Defects. www.cdc.gov/ncbddd/heartdefects/data.html. Accessed on May 1, 2014.
Hoffman JL. J Am Coll Cardiol. 2002;39:1890-1900.
Kurobe H. Stem Cells Transl Med. 2012;1:566-571.