Continuing Education Activity

Transmyocardial laser extravascular angiogenesis (TMLR) has emerged as an option in patients suffering from chronic refractory angina that can improve both patients’ symptoms, exercise capacity, quality of life, and decrease their cardiac rehospitalization. This activity on transmyocardial laser extravascular angiogenesis reviews and highlights the role of interprofessional teams in evaluating and treating patients with refractory angina pectoris that have failed all other therapeutic options.

Objectives:

• Identify the etiology of refractory angina pectoris.
• Describe the appropriate evaluation of patients undergoing transmyocardial laser extravascular angiogenesis.
• Outline the procedure of transmyocardial laser extravascular angiogenesis.
• Discuss interprofessional team strategies for improving care coordination and communication to advance transmyocardial laser extravascular angiogenesis and improve outcomes.

Introduction

Worldwide, a significant number of patients have coronary artery disease (CAD). Many such patients end up with heart failure or impaired myocardial function from ischemia or obstruction resulting from multivessel atherosclerosis.[1][2] There have been many advances in both pharmacological and myocardial revascularization techniques. As a result, the survival of patients has increased after myocardial infarction, which has led to an increased number of patients with debilitating symptoms of chronic refractory angina and ischemic heart disease.[3][4] Refractory angina pectoris is chronic angina that is not responsive to maximum medical therapies and standard revascularization via coronary artery bypass (CABG) surgery or percutaneous coronary angioplasty (PCA).[5]

A subgroup of ischemic heart disease and angina patients can not be treated successfully despite optimal medical management and standard revascularization. For these patients, some advanced therapeutic options have been clinically tested, including transmyocardial laser revascularization, transcutaneous electrical nerve stimulation, or angiogenesis by gene or cell therapy.[6]

Transmyocardial laser extravascular angiogenesis (TMLR) has emerged as an option in patients suffering from chronic refractory angina that can improve both patients’ symptoms, exercise capacity, quality of life, and decrease their cardiac rehospitalization.[2][7] TMLR was approved by the US Food and Drug Administration (FDA)  in 1998 to treat moderate to severe angina that occurred due to CAD, and that is nonresponsive to standard revascularization and maximal medical therapy.[4] However, this technique was already in clinical use starting in 1983 in association with CABG as a hybrid technique. In this procedure, the laser is used directly on the surface of the heart to revascularize it.[4]

It is important to note that recently all the trials pertaining to TMLR have been closely examined. It was also found that many studies that assessed subjective improvement fromTMLR lacked blinding. Many randomized clinical trials that examined TMLR also did not use important pre-defined outcomes such as myocardial infarction, arrhythmia, or congestive heart failure, which are examined in most practice-changing RCTs in cardiology. Based on current guidelines, for the management of refractory angina, the ACC/AHA guidelines do not recommend TMLR with or without CABG.[8][9][10]

Etiology

As mentioned above, transmyocardial laser extravascular angiogenesis (TMLR) is used in patients with refractory angina. Refractory angina is caused by ischemic heart disease. TMLR is explicitly indicated in patients where CAD causes angina. For example, per ACC/AHA guidelines published in 2012, there is a class 2b indication for using TMLR as sole therapy in patients with disabling, medically unresponsive refractory angina with no other options available. The same guidelines indicate that TMLR-CABG combination does not improve survival in refractory angina patients. However, there may be a benefit in selected patients to relieve angina.[8] Currently, TMLR is only for the clinical trial purpose as a last resort, especially since the invention of newer noninvasive therapy like ranolazine.[11]

Epidemiology

In the United States (U.S.), above 15.4 million cases of symptomatic CAD, with 400,000 cases newly diagnosed annually. Approximately 300,000 to 900,000 patients are estimated to have refractory angina pectoris, with new 25,000 to 100,000 cases diagnosed every year.[3][5][12]

Per one study, more than 20,000 cases of transmyocardial laser extravascular angiogenesis (TMLR) were performed in the U.S. alone, and more 50,000 cases of TMLR were performed worldwide by 2014.[4]

History and Physical

These patients with refractory angina that can undergo transmyocardial laser extravascular angiogenesis (TMLR) are those that are unable to perform daily routine activities such as climbing stairs, walking a block, or cleaning the furniture in the house without experiencing chest pain. Their quality of life is poor, and they have reduced life expectancy. These patients have quit smoking and have already tried multiple times optimal medical management therapies and standard revascularizations. When there is no available option left to relieve symptoms of angina, TMLR is available.[5]

On physical exam, there is no specific constellation of findings that indicated refractory angina that needs TMLR. In general, cardiac examination should be done. Usually, these patients will show signs and symptoms of stable angina. They have episodic chest pain from stress or exertion. During an episode, they can also experience tachycardia, hypertension, diaphoresis, anxiety. They can have S3 or S4 sounds on physical examination. EKG must be obtained in any patient that comes in with chest pain. EKG for these patients might show transient ST-segment depression or no findings at all.[13][14][15]

Evaluation

Only patients who have already failed all therapeutic options available for refractory angina will be evaluated for transmyocardial laser extravascular angiogenesis (TMLR). It is important to carefully consider risks and benefits for each case as TMLR is not recommended for refractory angina. Evaluation for this procedure will likely involve basic cardiac evaluation. Patients should have basic labs such as complete blood count and complete metabolic panel check. An ECG should be performed. Depending on the comorbidities of the patient other tests such as echocardiography, magnetic resonance imaging, or coronary angiography may be performed to accurately assess the risk and benefits of this procedure for the patient peri-operatively.[16][17][18]

Treatment / Management

As discussed earlier, transmyocardial laser extravascular angiogenesis (TMLR) is performed in a particular group of patients. TMLR is a technique where a laser beam is used to create small channels on the surface of the heart. To allow access to the heart, a patient first undergoes anterior thoracotomy at the left fifth intercostal space. This generally causes the epicardial surface of the left ventricle and pericardium to be accessible. Based on how big the ischemic region of the heart is, a laser beam is used to create 20 to 40 microchannels, each 1 mm in width and 1 cm apart, from inferior to apex, then lateral and then the anterior surface of the epicardium. Then the chest tube is placed, and the incision is closed off—the majority of the time, the patient is extubated inside the operative room. Two different laser systems can be used in TMLR that are FDA approved. One is the carbon dioxide (CO2), and the other is the holmium: yttrium–aluminum–garnet (Ho: YAG) laser system.

The CO2 laser system works by a generation of infrared light to ablate the myocardial tissue. It is only delivered on beating heart, so laser pulsations are matched with r waves on ECG to avoid causing the arrhythmia. The Ho: YAG laser, on the other hand, is manually advanced a fiber optic bundle through the myocardium while the laser fires.  The most widely accepted theory about how TMLR causes short term and long term angina relief is as follows. Nociceptors that allow pain perception and afferent fibers transmit sensory information to the brain are located in the superficial myocardium that is easily accessible to the laser.

TMLR is thought to ablate these nociceptors and afferent fibers blocking the pain signaling. Besides, denervation at the myocardium leads to decreased production of norepinephrine at the myocardium, which leads to decrease inotropy and reduced oxygen demand of the heart, which results in angina relief. In the long run, angiogenesis is induced through inflammatory and vasculogenic mechanisms, which lead to increased vascular network at the site where laser channels were created leading to long-term angina relief. For instance, a study has found that after TMLR the myocardium has sustained increased VEGF release that is involved in inducing angiogenesis.[2][19][20][21]

This procedure if performed alone takes about 2 hours. Patients are usually admitted to the cardiac intensive care unit and they stay anywhere from 4 to 7 days after the procedure in the hospital. Patients should generally be restarted on all their cardiac medications the same day after the procedure.

Differential Diagnosis

Since transmyocardial laser extravascular angiogenesis (TMLR) is only performed in patients with refractory angina, usually other conditions that can mimic angina should be ruled out. It is essential to ensure that a patient's angina is not any other condition that mimics angina symptoms. Differential diagnosis of angina is broad. However, for conditions that can mimic refractory angina, only differential diagnoses that are also chronic and recurrent should be considered. For instance, gastrointestinal causes like gastroesophageal reflux disease, hiatal hernia, musculoskeletal conditions like muscle spasm, costochondritis, or psychological disorders like anxiety or panic-induced chest pain are all conditions that can be recurrent and not responsive to standard anti-anginal medical therapy.[21]

Prognosis

Prognosis after transmyocardial laser extravascular angiogenesis (TMLR) is variable. According to one study, survival after the TMLR procedure is 64 percent five years after the procedure, while another study found a survival rate as high as 80% at ten years.[22] Even in patients that survive long after the procedure, angina is known to return in 3 years, and cardiac complications are most commonly observed.[23]

Complications

The most common complications after transmyocardial laser extravascular angiogenesis (TMLR) are cardiac. After TMLR, patients can experience myocardial infarction, ventricular arrhythmia, atrial fibrillation, left ventricular dysfunction, or heart failure.[9] Other rare complications are cerebral microembolism, cerebral vascular accident, pneumonia, sepsis, and death.[24] These complications are common in patients having diabetes mellitus, angina, untreated left anterior descending (LAD) coronary artery disease.[25][26]

Deterrence and Patient Education

The importance of medication compliance, laboratory tests, and imaging workup, regular follow-up at the appointments, especially primary care provider, cardiothoracic surgery, and cardiology follow-up, should be stressed. Time should be taken to clearly explain to the patient the risk versus benefits of the treatment. The patient should honestly be told the current evidence regarding the benefits of this treatment and why this treatment is considered an option for him or her. The patient should be given an idea about the prognosis, and discussion about the code status and advance directives should occur.

Enhancing Healthcare Team Outcomes

An interprofessional team that provides a holistic and integrated approach to care can help achieve the best possible outcomes. Based on the type of patient population involved in refractory angina, different specialist involvement can improve the outcome for the patient.

The primary care provider, cardiologist, and cardiothoracic surgeon should have excellent internal communication to provide optimal care. The pharmacist should be consulted to make sure that the patient is restarted on all the cardiac medications that he or she was on before the surgery. If the patient has multiple comorbidities and expresses a desire to focus on comfort care, then palliative care should be involved. The palliative care team, patient, and the family should have a good discussion of options of care in the future considering the mortality burden on a patient on a case by case basis. [Level 1]