Transmyocardial laser revascularization fell somewhat out of favor in the 1990s, but recent developments have inspired new research into the technique. A laser technique that uses pulses of infrared light to blast channels into the heart muscle has long been the last hope for patients whose arteries are so clogged and constricted that they cannot benefit from bypass surgery. The technique, called transmyocardial laser revascularization, or TMR, has remained a niche procedure for 20 years, practiced only on patients with no other options. In transmyocardial laser revascularization, lasers vaporize a tube of heart muscle and injure a zone of heart tissue surrounding that tube, causing either new blood vessels to develop or denervation. Courtesy of CryoLife. But recent advances in stem cell research have inspired a new dimension to TMR therapy. Following up on promising research done in Europe, planned studies in the US will combine TMR with stem cells to spur new blood vessel growth. Crocodile hearts TMR originally was inspired by crocodile hearts, which do not have blood vessels but simply channels allowing blood to flow through. When TMR was first developed in the 1970s and ’80s, it was not laser-based: Needles sometimes were used to poke holes to increase direct blood flow from the ventricle – the part of the heart that collects blood and then expels it into the arteries leading to the lungs and body – into the heart muscle, or myocardium. But scar tissue quickly closed up the holes, and it was obvious that a different technique would be needed. Surgeons began to use lasers instead. The lasers could vaporize a tube of myocardium and injure a zone of heart tissue surrounding the tube. The idea was that the injured zone would develop new blood vessels as it healed, a process called angiogenesis. The new blood vessels would bring more blood flow to the myocardium, decreasing pain and increasing function. Another explanation of TMR posits that the lasers damage nerve tissue. Fewer nerves in the heart muscle mean less pain for the patient. It is possible that both angiogenesis and denervation occur, but cardiac surgeons hope that angiogenesis is the dominant effect, as it would lead to truly improved heart function. Transmyocardial laser revascularization traditionally is performed through a large opening in the chest (a). But the small, flexible fiber used by the Ho:YAG laser also can perform the procedure through small ports in the chest (b). Courtesy of CryoLife. Originally, many lasers were evaluated for TMR, but not all had the same effect. An animal study comparing two infrared lasers with an ultraviolet excimer one found an improvement in myocardial blood flow only in procedures done with the infrared lasers. Two infrared lasers currently are used for TMR: the holmium-doped yttrium aluminum garnet (Ho:YAG) solid state produced by CryoLife Inc. of Kennesaw, Ga., and the CO2 manufactured by Novadaq Technologies Inc. of Mississauga, Ontario, Canada. Both completely ablate a tube of muscle tissue in the myocardium and then injure a zone around it. However, their wavelengths are different, as is the experience a surgeon has using them in the operating room. Novadaq’s 800-W CO2 laser uses a gas discharge as the active gain medium and emits light at 10.6 µm. That wavelength is absorbed by almost everything, especially water. Human tissue, being mostly water, absorbs the light, heats up and vaporizes. The difficulty in making a CO2 laser is in finding optical materials that transmit the wavelength instead of absorbing it; the company’s Heart Laser 2 uses zinc selenide for the lens. The Heart Laser 2 from Novadaq Technologies is an 800-W carbon dioxide laser that emits light at 10.6 µm. In the operating room, the surgeon moves an articulated arm containing mirrors to guide the laser light, placing the tip of the arm directly on the heart’s left ventricle. Courtesy of Novadaq Technologies. In the operating room, the surgeon using the CO2 laser moves a long, articulated arm containing mirrors to guide the laser light, placing its tip directly on the heart’s left ventricle wall. The laser pulses just once to make a channel, timed to come between beats, when the heart is still full. This reduces the chance of arrhythmias. The surgeon usually makes 10 to 25 channels, a procedure that takes about 5 min. The CO2 laser vaporizes the tissue in a single shot, and some of its fans believe it makes a cleaner channel through the tissue, with less scarring than with a Ho:YAG. The reason is the different wavelength of light used. Tissue strongly absorbs the 10.6-µm wavelength; time-lapse photography shows the cells vaporizing layer by layer in a neat tube as the light pulse moves through the heart tissue. The Solargen Ho:YAG laser, developed by Cardiogenesis Corp., a CryoLife Co., has a 2.1-µm wavelength that spreads more laterally through the tissue, affecting more volume of heart muscle than the CO2 laser. Its proponents say this is one of its virtues; by affecting more tissue, it causes more inflammation and a stronger healing response. The Ho:YAG laser from CryoLife produces light with a wavelength of 2.1 µm, firing it in 5-Hz pulses; the surgeon directs the light into the heart muscle through a fiber. Courtesy of CryoLife. Keith A. Horvath, director of the Cardiothoracic Surgery Research program within the National Heart Lung and Blood Institute at the National Institutes of Health (NIH) in Bethesda, Md., prefers the CO2 laser. He said that tissue samples from hearts treated with the Ho:YAG show new blood vessel development sealed within zones of scar tissue. One way to explain this scarring pattern is through surgeon error. The laser pulses and ablates a small amount of tissue at a time, advancing into the void created. If the laser fiber is pushed past the void, damaging the muscle tissue beyond before it pulses again, that could create the pattern of alternate scarring with blood vessels. Tissue samples from hearts treated with the CO2 laser show much less scarring, Horvath said. Proponents of the Ho:YAG laser have nothing negative to say about the CO2 laser, save that it is bulkier and less convenient to use. “I think they both work. The holmium is easier to work with,” said Keith B. Allen, director of surgical research at St. Luke’s Mid America Heart and Vascular Institute in Kansas City, Mo. He cites long-term studies showing patient improvement with either type of laser. The Ho:YAG laser produces light with a wavelength of 2.1 µm and fires in pulses at 5 Hz. The laser light is directed into the heart muscle through a fiber held by the surgeon. Each light pulse vaporizes a tube of tissue about 1 mm thick. The surgeon advances the fiber 1 mm into the void created, and then the laser fires again. It pulses quickly enough that the motion of the laser’s fiber into the heart feels continuous to the surgeon. The Sologrip III Ho:YAG laser handpiece is used for transmyocardial revascularization during open-heart surgery. Courtesy of CryoLife. When coaching surgeons to use the device, “the analogy I use is the rate it takes a hot knife to drop through a stick of soft butter,” Allen said. Both Allen and David C. Gale, CryoLife’s vice president of research and development, dismiss as fiction the idea that a surgeon could accidentally shove the fiber ahead of the vaporized zone, bluntly damaging heart tissue. The fiber is too flexible to push into the myocardium, Gale said. With just the two laser makers – Novadaq and CryoLife – competing for market share, there is ongoing disagreement over which laser works best. But proponents on both sides of the debate generally agree that the procedure works. “There’s always been this argument: ‘Which is the better laser?’ ” said Robert I. Rudko, one of the original designers of the carbon dioxide heart laser. “But we don’t know how [the healing mechanism] works. Nobody knows exactly what’s going on after the laser does what it does. “And if you don’t know how it works, it’s hard to say which is most effective.” Stem cells Approximately 2500 TMR procedures are performed in the US each year, most in combination with bypass surgery. Patients often have one area of the heart that is operable, while other areas are not; the inoperable areas are treated with TMR. The market for bypass plus TMR could be significantly larger, but many cardiologists are skeptical of the therapy’s benefits. TMR suffered a blow to its credibility in the late 1990s when a high-profile study found the procedure had primarily a placebo effect. Some manufacturers quit making lasers for TMR, and the procedure’s popularity shrank. But cardiac surgeons say the skepticism is unwarranted. The study that found only a placebo effect did not practice standard TMR, and it does not reflect the therapeutic benefit of the properly performed therapy, Horvath said. Despite the uncertainty surrounding exactly how TMR works, cardiac surgeons are convinced that it does stimulate the formation of new blood vessels in the heart muscle.1 And two new studies could enhance TMR’s healing potential by combining the laser work with stem cells. Horvath’s lab at NIH is recruiting patients for a study that will combine CO2 laser TMR with mesenchymal stem cells, which originate from connective tissue and which can differentiate into several types of adult cells, including those that form blood vessels or muscle. His study will harvest a patient’s mesenchymal cells from his/her bone marrow, then culture them for three weeks to grow enough for the procedure. A surgeon will perform TMR and then inject the mesenchymal cells into the patient’s heart tissue to jump-start angiogenesis in the areas damaged by the laser. The hope is that patients treated with their own stem cells will grow more and better blood vessels than patients treated with plain TMR and, potentially, new heart muscle as well. The additional blood vessels should bring more oxygen to that area of the heart muscle, increasing heart function and decreasing pain. The study will track patients’ progress annually for five years. Allen plans a similar study for the Ho:YAG laser. After TMR, researchers will inject stem cells taken from the patient’s own bone marrow into the injured tissue immediately bordering the vaporized channel in the heart muscle. The injection will be carried out using CryoLife’s new Phoenix, a set of three retractable needles that sit in a shaft surrounding the laser fiber until needed. This study is awaiting FDA approval. But similar work has been successful in Europe, as reported recently in the European Journal of Cardio-Thoracic Surgery.2 The TMR-stem-cell therapy could be a game-changing technology that convinces cardiologists once and for all that TMR really does work. More awareness of the procedure by cardiologists could improve the lives of those with debilitating heart disease who formerly were considered to be inoperable, no-option patients. References 1. K. Allen et al (September 2008). Transmyocardial laser revascularization: From randomized trials to clinical practice. A review of Techniques, evidence-based outcomes, and future directions. Anesthesiol Clin, Vol. 26, pp. 501-519. 2. G. Reyes et al (2009). Bone marrow laser revascularisation for treating refractory angina due to diffuse coronary heart disease. Eur J Cardiothorac Surg, Vol. 36, pp. 192-194.