Transmyocardial Laser Revascularization

Despite advances in both medical and surgical management of coronary artery disease (CAD), many patients remain symptomatic after conventional therapies have been exhausted. Typically, these patients continue to have chest pain while on maximal medical therapy, and most are at an extraordinary risk for surgical intervention.

Transmyocardial laser revascularization (TMLR) is based on the use of a high-powered carbon dioxide or other laser that interjects a strong energy pulse into the left ventricle, vaporizing the ventricular muscle and creating a transmural channel with a 1-mm diameter. The precise physiologic mechanism for its efficacy is not thoroughly understood.

Although coronary artery bypass grafting (CABG) is effective in many patients, some are not candidates for direct revascularization procedures. TMLR has elicited growing interest for the treatment of otherwise surgically untreatable CAD. Several large clinical studies have shown marked improvements in angina. These improvements appear instantaneously after TMLR and are sustained. In most cases, a comparable improvement in exercise tolerance occurs. Regional myocardial perfusion also may be improved, but this has not been convincingly confirmed on thallium scintigraphy.

The marked improvement in patients with chronic angina led the US Food and Drug Administration (FDA) to approve TMLR for such use. In addition to the carbon dioxide laser energy source, alternative devices using the yttrium-aluminum-garnet (YAG) and excimer lasers have been studied. ^[1]  The latter two sources employ fiberoptic technology and are being evaluated for percutaneous approaches.

The first attempts at improving myocardial blood supply were designed to increase collateral circulation from extracardiac sources. In 1935, Beck used a burr to drill holes into the epicardium and pericardium, intending to stimulate ingrowth of new vessels into the ischemic myocardium.

In 1941, Schlesinger et al observed that intramyocardial arterioles were not prone to arteriosclerosis. This prompted Vineberg to implant the left internal mammary artery (LIMA) directly onto the myocardium with the purpose of developing collaterals between the LIMA and the intramyocardial arterioles. Although the first patient to undergo the Vineberg procedure died 2 days later, the LIMA was found to be widely patent at autopsy. Vineberg later created an intramyocardial tunnel prior to LIMA implantation, and patency of these grafts was documented two decades later.

In 1965, Sen et al studied the benefits of transmyocardial channels produced with needle punctures. Using a canine model, they placed numerous needle punctures in an ischemic area subtended by an occluded left anterior descending artery. They showed that the acupuncture-created channels resulted in decreased mortality, increased long-term survival, and decreased infarct size. Although patent channels were identified at 8 weeks, no evidence suggested that the channels had developed an endothelial cell lining, thus confirming successful rearterialization.

In 1968, Sen et al described marked improvements in patients with chronic angina following transmyocardial revascularization. These initial data supported attempts to improve myocardial perfusion by creating mechanisms for a direct flow of blood from the ventricular cavity to the myocardium, thus mimicking the anatomy of the reptilian heart, in which much of the myocardium is perfused with blood directly from the ventricular cavity.

During the next two decades, numerous studies were undertaken to evaluate the effects of needle-created transmyocardial channels in revascularizing ischemic myocardium. However, much of this research received little attention because it was not considered nearly as promising as the emerging techniques involving direct myocardial revascularization, such as CABG and angioplasty.

The development of laser energy sources in the 1980s stimulated investigators to restudy myocardial acupuncture. In 1981, Mirhoseini et al demonstrated that the carbon dioxide laser could generate small transmyocardial channels in the ischemic myocardium of a dog. In 1983, Mirhoseini et al used TMLR on a patient with CAD, employing  a carbon dioxide laser in conjunction with CABG to treat a hypokinetic area of the left ventricle. The patient did well, with normal ventricular function demonstrated during a postoperative nuclear scan.

These initial clinical studies provided further impetus for the use of TMLR. ^{[2, 3, 4, 5]} Since the early 1990s, carbon dioxide laser systems have been used to perform TMLR in humans, with excellent results. Holmium:YAG TMLR has also been approved by the FDA. ^[6]

To date, more than 50,000 TMLR procedures have been done worldwide, nearly one third of them done in the USA alone. Over the past two decades, multiple studies have reported good-to-moderate outcomes. ^[7]

For patient education resources, see the Heart Health Center, as well as Angina Pectoris and Heart Disease Health Center.

Although no absolute indications have been described for the application of TMLR, several studies have provided some necessary guidelines.

Most patients have diffuse disease, either locally or globally, such that no target vessel is available for either percutaneous transluminal coronary angioplasty (PTCA) or bypass grafting. Furthermore, the appropriate patient is symptomatic from disease in an area of the myocardium that is not treatable by conventional techniques and has not responded to maximal medical therapy.

Before TMLR is undertaken, a nuclear perfusion scan is obtained, the results of which must show evidence of reversible ischemia. Patients with infarcted or scarred tissue are not suitable candidates for TMLR. Patients should have reasonable ventricular function, with left ventricular ejection fraction (LVEF) above 20%.

Historically, patients enrolled in TMLR clinical trials had severe CAD with Canadian Heart Association class III or IV angina despite maximal medical therapy. The patients had an LVEF above 20% and were on maximal antianginal therapy.

The reported mortality (7-10%) following TMLR is a significant cause for caution. Risk-factor assessment has shown that patients with unstable angina and poor myocardial function are at relatively greater risk. If patients have an LVEF greater than 30% and chronic stable angina, their risk may be minimized.

In addition, patients must have a viable region of the myocardium for TMLR. Patients with scarred or infarcted tissue are not appropriate candidates. Patients with severe adhesions from prior coronary artery bypass surgery can have significant bleeding if a median sternotomy approach is used; therefore, in these patients, a left anterior thoracotomy may be an alternative.

Initially, researchers believed that two components were necessary to the success of TMLR for revascularizing myocardium. The first component was thought to be a physical effect: TMLR channels were thought to remain patent secondary to the high intraluminal pressure within the left ventricle. These patent channels would become small sinuses from which diffusion could occur deep within the once-ischemic myocardium and from which cardiac capillaries could communicate and draw oxygen.

This subject has been an area of debate, and histologic data have been controversial. Some researchers have observed patency in these channels for a 2-week period, followed by complete occlusion in humans. In animal models, postoperative patency has been achieved for more than 12 months. Gassler et al, describing the histologic features of TMLR at autopsy at various time intervals, ^[8]  showed that no patent channels were created and that endothelialization did not occur. Thus, they concluded that the histologic steps following TMLR are much like those of wound healing following necrosis, resulting in a fibrous scar. They did not describe the clinical response to TLMR in these patients prior to death.

Stimulated by the ongoing debate over the long-term patency of laser channels, several centers reported results of histologic analyses of tissues from patients who died after TMLR. To date, no researchers have reported patent channels from clinical material. Early development of a capillary network has been observed, but the results have not been consistent. Some believe that angiogenesis resulting from the inflammatory response, as opposed to the patent channel hypothesis, may be the reason for improved perfusion.

The second component of successful TMLR is based on the hypothesis that the laser channels activate wound repair mechanisms, thus resulting in increased angiogenesis. This hypothesis is supported by Gassler et al, ^[8] who noted extensive capillary networks around the laser-created channels in histology sections from a patient 150 days after surgery. The formation of a fibrous scar and the development of capillary networks suggest that the laser actually necroses myocytes, thereby initiating an inflammatory response that, in turn, results in angiogenesis and improved myocardial microperfusion.

A proposed explanation for the success of TMLR is that the process of using a laser to create channels in the ischemic area of the left ventricle actually causes denervation of the myocardium.

Sundt and Kwong noticed a significant decrease in patient symptoms after TMLR. Using the holmium:yttrium-aluminum-garnet (YAG) laser, they performed laser revascularization in canine hearts. Microscopic analysis revealed that laser treatment of the heart tissue might damage or even destroy nerve fibers and thus reduce the symptoms of angina. However, if this were the sole reason for the initial success of TMLR, the long-term outcomes would not be positive, because the original problem of ischemic myocardium would continue to worsen.

Denervation may play a role in the success of TMLR, depending on the type of laser utilized, but the positive effects of denervation are in addition to the increased blood flow that occurs over time in relation to the other mechanisms of action that make TMLR a successful therapy.

Transesophageal echocardiography (TEE) is used to confirm the accurate formation of transmural channels, which occur as a result of vaporization of the red blood cells within the myocardial wall. It is important to have resuscitative equipment in the operating room because touching of the myocardium and generation of the laser beam can sometimes trigger ventricular arrhythmias.

Most clinical studies show that TMLR, regardless of the type of laser used, results in profound and almost immediate improvement in angina pectoris among patients with inoperable CAD. This improvement appears to be sustained throughout the first year. TMLR also offers advantages over CABG in that it does not require arresting the heart or instituting cardiopulmonary bypass (CPB).

A review of TMLR by the FDA recommended that TMLR not be considered experimental, because the latest data support its efficacy and safety. Clinical trials are in progress that randomize patients to continued medical therapy or to TMLR. A 2015 Cochrane review of TMLR versus medical therapy for refractory angina concluded that overall, the risks associated with TMLR outweighed the potential clinical benefits. ^[9]

Combining CABG with TMLR has led to the improvement of symptoms without added risks. ^[10]  Only about 5% of TMLR procedures a year are performed with a minimally invasive thoracoscopic technique. ^[11]

TMLR may prove helpful in the treatment of cardiac transplantation patients with diffuse atherosclerosis. 

The use of TMLR via the endocardial approach is an important subject of clinical study. TMLR performed via the endocardial approach creates transmural channels through the myocardium, initiated at the endocardial surface and extended toward the pericardium, by using the holmium:YAG laser. The obvious benefits of this technique are that it can be performed via a percutaneous approach in the cardiac catheterization laboratory and that it obviates the need for surgery.

A robotically assisted completely endoscopic approach to TMLR was found to be feasible and effective in a study of 42 patients with Canadian Cardiovascular Score class IV angina at baseline. ^[12]   

Clinical investigations are evaluating alternative energy sources potentially adaptable to endovascular applications. The final use of this type of treatment, whether delivered percutaneously or surgically, will be determined only when the results of prospectively randomized trials of maximum medical therapy versus TMLR are available and the impact of this therapy on survival and symptom relief are known.

Clinical experience

Numerous studies have reported on the use of TMLR. ^{[13, 14]} In most patients, preoperative and postoperative evaluations include positron emission tomography (PET), dobutamine echocardiography, thallium stress testing, radionuclide ventriculography, and an exercise treadmill test to evaluate the results of TMLR. Thallium dipyridamole scans and dobutamine stress echocardiograms have shown an overall definite, statistically significant reduction in the severity and extent of ischemic myocardium and improvements in resting function and contractile reserve.

Without question, the most dramatic clinical effect of TMLR has been a significant reduction in angina pectoris. In patients with Canadian Heart Association stage III or IV angina, perioperative mortality was 9%. Postoperatively, most patients improved to class II or better. Remarkably, much of this benefit was observed immediately after the operation.

In multicenter studies, one third of patients reported complete relief of angina, whereas two thirds experienced at least a two-class reduction in symptoms. In addition, the admission rate for angina pectoris in multicenter series dropped significantly in patients treated with TMLR. Note that myocardial perfusion, as determined by single-photon emission computed tomography (SPECT), was significantly improved in ischemic areas that had received TMLR.

Long-term studies have unequivocally demonstrated the superiority of TMLR in decreasing angina. Five-year follow-up of patients who had refractory class IV angina and were not candidates for conventional therapy demonstrated significantly increased Kaplan-Meier survival estimates in patients randomized to TMLR. The significant angina relief observed 12 months after sole TMLR therapy was sustained over the long term and continued to be superior to that observed for patients maintained on continual medical management alone.

Several large studies have thus shown that patients who undergo TMLR have both short- and long-term relief from angina. At least 30% of patients tend to have relief from angina at 5 years. However, patient selection is important; not all patietns will benefit from this procedure. Patients with unstable angina tend to have higher mortality following surgery than patients managed with nitroglycerin or heparin. Other factors that adversely affect mortality include the following:

• Advanced age
• Decompensated heart failure with a low ejection fraction
• Ongoing myocardial ischemia

On the basis of on these findings, current Society of Thoracic Surgeons (STS) practice guidelines classify TMLR as sole therapy for unstable angina as a class llB indication. Some have advocated percutaneous TMR for this patient population, but several randomized trial have not yielded any clinical benefit.

Improvements in myocardial perfusion after TMLR have been less convincing than its impact on clinical symptoms. ^[15]  Study findings have not been uniform, with most showing no difference between baseline and 12-month studies of ejection fraction using nuclear studies. In addition, studies have not defined major differences in short-term morbidity and mortality between the holmium:YAG laser and the CO₂ laser in the setting of TMLR. ^[16]

TMLR has also been used in cardiac transplantation patients who have accelerated graft atherosclerosis documented by angiography findings. Angiograms revealing patency of channels after TMLR in symptomatic patients have been described. ^[17]

Reports indicate that TMLR provides excellent relief of angina in these patients. Clinical trials have been initiated in many centers in the United States and Europe.

TMLR has been combined with intramyocardial autologous endothelial progenitor cell injections for angina relief. To date, studies have only included a small number of patients, and the follow-up has been short. The one conclusion derived from the study is the great caution should be exercised when this therapy is employed in patients with depressed left ventricular function. ^[18]

CABG combined with TMLR

Over the past few years, increasing evidence has shown that TMLR may be more useful as a hybrid procedure when used in combination with CABG. Several randomized studies have shown that the combination of TMLR and CABG yields more clinical benefit than TMLR or CABG alone. In a prospective, randomized trial involving 263 patients who were not completely revascularized with CABG alone, the addition of TMLR to conventional CABG provided superior anginal relief as compared with CABG alone.

Other studies have shown similar results. When TMLR was used (both alone and in combination with CABG), substantial improvement was noted with regard to the anginal score, exercise tolerance, and left ventricular function 6 months after the procedure. In summary, most studies have shown that TMLR, as an adjunct to CABG in selected patients with limited options, may improve hospital outcomes.

Percutaneous TMLR

Traditonally, TMLR has always been done by opening the chest. To reduce the morbidity of surgery and anesthesia, a minimally invasive percutaneous approach to TMR has been attempted. Both radial artery and femoral artery approaches to the left ventricle have been undertaken. The laser fiber is then guided by electrical mapping and used to create 2- to 3-mm small pockets in the subendocardial tissue.

To date the results from small series of percutaneous TMLR have not been impressive. There appears to be a high rate of periprocedural adverse events such as bleeding and even tamponade. The key reasons why percutaneous TMLR has not been successful are that the technique only permits creation of a few holes and that locating the exact lesion within the beating myocardium is difficult. ^[19]

TMLR with stem cell therapy

Over the past decade, many studies have looked at the use of stem cells to regenerate infarcted myocardium. Several animal and human studies have evaluated TMLR in conjunction with delivery of stem cells. Isolated reports indicate that this therapy is safe and can even improve the angina class. However, these studies should be considered experimental, in that they have many limitations with respect to delivery, type of differentiation, and outcome evaluation. A small clinical trial has assessed the effects of TMLR with injection of autologous mesenchymal stem cells. ^{[20, 14]}