Chronic effects of transmyocardial laser revascularization in the nonischemic myocardium: a word of caution

BACKGROUND: Transmyocardial laser revascularization (TMLR) has been shown to induce angiogenesis and improve regional myocardial blood flow. However, the biological response to laser of different energy doses in nonischemic myocardium has not been well studied. We study the time course of histological appearance following high- and low-energy TMLR in a rodent model of normal myocardium. METHODS: The animals were randomized to two groups (high-energy (1.4 J/pulse) TMLR group and low-energy (0.6 J/ pulse) TMLR group). TMLR was applied to the anterolateral wall of the left ventricle. Then the animals were sacrificed (one every 2 or 3 days up to 6 weeks, then one every week) to give a series of hearts from 1 week to 12 weeks following TMLR. RESULTs: No patent laser channels were identified. All laser channel remnants were composed of granulation tissue, fibrosis, and various amounts of vascular structures. Changes in vascular density demonstrated a similar pattern in both groups over time. The initial increase in vascular density within the laser channel remnants and the surrounding areas was more marked in group I than in group II. Gradual decline of vascular density occurred during a later follow-up. More fibrosis and less vasculature were demonstrated 12 weeks after laser therapy in group I. CONCLUSION: Angiogenic response to the Holmium:YAG laser in the nonischemic myocardium is nonspecific and unsustainable. TMLR might chronically impair the myocardium function by enhancing regional scar formation. Therefore, we should clearly identify the ischemic area for laser therapy. Reduction of laser energy might prevent this potential complication.     

Noninvasive characterization of myocardium after transmyocardial laser revascularization

AIM: The therapeutic mechanism of transmyocardial revascularization (TMR) is not yet fully understood, and continues to be a subject of controversy and active research. Immediate direct laser channel flow, gradual angiogenesis, denervation, and perioperative infarction of the ischemic area have been all discussed, without clear evidence indicating superiority of individual factors. METHODS: We utilized a prospective noninvasive physiologic dynamic method to assess laser-related myocardial injury. The study protocol included EKGs and echocardiograms, including intraoperative transesophageal echocardiograms (TEE) on consecutive TMR patients. CPK-MB was measured postoperatively, with 5 samples at 6-hour intervals. RESULTS: Fifty male patients averaging 62 years old were enrolled in the study. Two patients experienced postoperative myocardial infarctions, from which 1 died. The average CPK-MB values were 12.8+/-1.28 immediately after surgery, 19.2+/-2.4 at 6 h, 15.2+/-2.3 at 12 h, 12.2+/-6.3 at 18 h, and 11.7+/-1.3 at 24 h. In only 5 patients were the CPK-MB values over 30 units at their peak. The intraoperative wall motion remained unchanged in the patients studied, both using TEE and transthoracic echography. CONCLUSION: Significant myocardial injury after TMR appears unlikely, as indicated by CPK-MB and myocardial wall dynamics. Furthermore, TMR does not seem to aggravate baseline myocardial ischemia. We found no evidence to support a hypothesis that surgical myocardial injury constitutes the mechanism of therapeutic action in TMR.     

Angiogenesis three months after clinical transmyocardial laser revascularization using an excimer laser.

BACKGROUND AND OBJECTIVE: We present for the first time histologic findings 3 months after clinical transmyocardial laser revascularization using a XeCl excimer laser. STUDY DESIGN/MATERIALS AND METHODS: Histology was performed on a patient who died from a noncardiac cause 3 months post-excimer TMLR. RESULTS: In the treated myocardium, no patent channels were found but scars were seen with a linear distribution and in continuity with circumscribed small fibrotic endocardial and epicardial scars. The scars were highly vascularized by new vessels, ranging from small capillaries to large thin walled, and sometimes branching ectatic vessels. Sprouting of vessels into the adjacent myocardium was also observed. CONCLUSION: These results suggest that angiogenesis might play a role in the clinical improvement after TMLR.     

Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia

Background. The mechanism of clinical improvement after transmyocardial laser revascularization (TMR) is unknown. One hypothesis holds that TMR causes increased myocardial perfusion through neovascularization. This study sought to determine whether angiogenesis occurs after TMR in a porcine model of chronic myocardial ischemia.

Methods. Six miniature pigs underwent subtotal left circumflex coronary artery occlusion to reduce resting blood flow to 10% of baseline. After 2 weeks in the low-flow state, dobutamine stress echocardiography and positron emission tomography were performed to document ischemic, viable myocardium. The animals then underwent TMR and were sacrificed 6 months later for histologic and immunohistochemical analysis.

Results. Histologic analysis of the lased left circumflex region demonstrated many hypocellular areas filled with connective tissue representing remnant TMR channels. Histochemical staining demonstrated a highly disorganized pattern of neovascularization consistent with angiogenesis located predominantly at the periphery of the channels. Immunohistochemical analysis confirmed the presence of endothelial cells within neovessels. Vascular density analysis revealed a mean of 29.2 ± 3.6 neovessels per high-power field in lased ischemic myocardium versus 4.0 ± 0.3 (p < 0.001) in nonlased ischemic myocardium.

Conclusions. This study provides evidence that neovascularization is present long term in regions of ischemic, viable myocardium after TMR. Angiogenesis may represent the mechanism of clinical improvement after TMR.     

Improved perfusion and contractile reserve after transmyocardial laser revascularization in a model of hibernating myocardium

Background. Transmyocardial laser revascularization (TMR) has been demonstrated effective for relieving angina, although prior studies have yielded inconsistent results regarding postoperative myocardial perfusion and function. This study evaluated long-term changes in myocardial perfusion and contractile reserve after TMR in a model of hibernating myocardium.

Methods. Miniswine had subtotal left circumflex coronary artery occlusion to reduce resting blood flow to 10% of baseline. After 2 weeks in the low-flow state, positron emission tomography and dobutamine stress echocardiography were performed to document ischemic, viable (hibernating) myocardium in the left circumflex distribution. Animals then had sham redo thoracotomy (n = 4) or TMR (n = 6). Six months later the positron emission tomography and dobutamine stress echocardiography studies were repeated.

Results. Myocardial blood flow in the left circumflex distribution as measured by positron emission tomography was significantly reduced in all animals after 2 weeks in the low-flow state. In animals that had TMR, there was significant improvement in myocardial blood flow to the lased regions 6 months postoperatively. No significant change in myocardial blood flow was seen in sham animals at 6 months. Dobutamine stress echocardiography after 2 weeks of low-flow demonstrated severe hypocontractility at rest in the left circumflex region of all animals, with a biphasic response to dobutamine consistent with hibernating myocardium. In animals that had TMR, there was a trend toward improved resting function and significantly improved regional stress function in the lased segments 6 months postoperatively, consistent with a reduction in ischemia. Global left ventricular wall motion at peak stress improved significantly as well. There was no change in wall motion 6 months postoperatively in sham-operated animals.

Conclusions. This study found improvements in myocardial perfusion and regional and global contractile reserve 6 months after TMR in a porcine model of hibernating myocardium. This improved perfusion and function likely accounts for the clinical benefits of the procedure.     

Effect of transmyocardial laser revascularization on chronic ischemic hearts in sheep.

BACKGROUND: We investigated the effect of transmyocardial laser revascularization (TMR) on myocardial function and regional blood flow in an animal model of ischemic heart disease. METHODS: Chronic ischemia was induced in 11 sheep by the application of coronary stenosis on the left anterior descending (LAD) and circumflex coronary artery (LCX). Ten weeks later, in six of them, transmyocardial channels were created in the anterior free wall and in the posterior wall of the left ventricle. Five animals served as controls. The myocardial function was assessed by echocardiography taken at baseline and every 2 weeks after coronary stenosis and after TMR. Myocardial perfusion was measured by colored microspheres, injected at baseline, immediately after coronary stenosis, before and after TMR, and at 20 weeks after coronary stenosis. The hearts were retrieved at 20 weeks for light microscopic examination. RESULTS: The left ventricular end-diastolic and end-systolic cavity area was elevated 20 weeks after coronary stenosis in the control and TMR groups. There was no difference between groups (analysis of variance; ANOVA, non-significant). The wall thickening fraction (WTF) decreased progressively and significantly after coronary stenosis in both groups. The WTF was further acutely reduced by TMR, and recovered gradually to the pre-TMR level. No significant difference in WTF was observed between the TMR and control groups. The resting myocardial blood flow was significantly increased by TMR at 20 weeks (P=0.03). Light microscopic examination revealed channel patency in 49% of the laser scars at 10 weeks post-TMR. A dense capillary network was observed at the edges of the surrounding scar. CONCLUSIONS: In an experimental model of ischemic heart disease, TMR developed angiogenesis in the lased channels, but, however, failed to improve myocardial function.     

Functional comparison of transmyocardial revascularization by mechanical and laser means

Background. As a result of the clinical benefit observed in angina patients treated by transmyocardial revascularization (TMR) with a laser, interest in mechanical TMR has been renewed. Although the injury induced by mechanical TMR is similar to laser TMR, the resultant impact on myocardial contractility is unknown. The purpose of this study was to determine whether mechanical TMR improves ventricular function as compared with laser TMR in chronically ischemic myocardium.

Methods. After establishing an area of chronic myocardial ischemia, 25 domestic pigs were randomized to treatment by: excimer laser (group I), a hot needle (50°C) (group II), a normothermic needle (group III), an ultrasonic needle (40 KHz) (group IV), or no treatment (group V). All devices create a transmural channel of the same diameter; 22 ± 1 transmural channels were created in each animal. Regional myocardial contractility was assessed by measuring ventricular wall thickening at rest and with dobutamine stress echocardiography. Six weeks after revascularization, the animals were restudied at rest and with stress. Postsacrifice and histologic analysis of angiogenesis and TMR effects was then assessed.

Results. Laser TMR provided significant recovery of ischemic myocardial function. This improvement in contractility after laser TMR was a 75% increase over the baseline function of the ischemic zone (p < 0.01). Mechanical TMR provided no significant improvement in function posttreatment. In fact, TMR achieved with an ultrasonic needle demonstrated a 40% worsening of the contractility versus the pretreatment baseline (p < 0.05). Histologic analysis demonstrated a significant increase in new blood vessels in the ischemic zone after laser TMR, which was not demonstrated for any of the other groups (p < 0.05). Additionally, evaluation of the mechanical TMR channels demonstrated significant scarring, which correlated with the functional results.

Conclusions. Using devices to create an injury analogous to the laser, mechanical TMR failed to improve the function of chronically ischemic myocardium. Only laser TMR significantly improved myocardial function.     

Surgical treatment of ischemic heart disease by transmyocardial laser revascularization

Results of transmyocardial laser revascularisation (TMLR) of the myocardium are analyzed. Two types of laser equipment were used domestic laser high-energy CO2 synchronized with patient's ECG, and XeCl laser Max-20. 32 patients underwent TMLR as a single method of surgical correction of the disease, 15 in combination with other methods of myocardium revascularisation. Obtained data testify that TMLR is a highly effective procedure in selective patients with IHD. Results confirm necessity of differential surgical policy for ischemic heart disease that permits to use adequate method of myocardium revascularisation for each patient.     

Guidelines for the clinical use of transmyocardial laser revascularization

Patients with chronic, severe angina refractory to medical therapy who cannot be completely revascularized with either percutaneous catheter intervention or coronary artery bypass graft surgery (CABG) are clinically challenging. Transmyocardial laser revascularization (TMR), as sole therapy or as an adjunct to CABG, may be appropriate therapy for these patients. The recommendations are based on a review of the available evidence including expert consensus opinions. The author follows the format of the American Heart Association and the American College of Cardiology guidelines for diagnostic and therapeutic procedures. There are class I indications for sole therapy TMR and class IIA indications for TMR as an adjunct to CABG. TMR is indicated for selected patients: as sole therapy for a subset of patients with refractory angina. It also may be effective as an adjunct to CABG for a subset of patients with angina who cannot be completely revascularized surgically.     

Wall motion and perfusion analysis of transmyocardial laser revascularization

OBJECTIVE: Transmyocardial laser revascularization (TMLR) creates channels in the myocardium. The aim of the treatment is to relieve angina in patients with end-stage coronary artery disease. We studied the effect of TMLR on myocardial function and perfusion with the combination of cine magnetic resonance imaging (MRI) and thallium scintigraphy. DESIGN: Eight patients with severe triple-vessel coronary artery disease were studied with MRI and thallium scintigraphy before and 6 months after laser treatment. RESULTS: TMLR did not improve global left ventricular (LV) function or myocardial perfusion. However, systolic wall thickening deprived in segments with fixed perfusion defects in 6 months and laser treatment prevented this deprivation (p = 0.03). In addition single photon emission computed tomography (SPECT) imaging indicated that TMLR prevented conversion of reversible into fixed defects. CONCLUSION: In severe, progressing coronary artery disease TMLR does not improve global LV function or myocardial perfusion, but it preserves systolic wall thickening in fixed defects (scar). It also prevents changes from ischemic myocardial regions to scar.     

Acute changes in functional and metabolic parameters following transmyocardial laser revascularization: an experimental study.

Today there is no doubt that angina in patients with diffuse end-stage coronary artery disease can be treated effectively by transmyocardial laser revascularization (TMLR). But until now, the underlying mechanism of TMLR is a matter of debate. The aim of this study was to investigate the immediate changes in functional and metabolic parameters after the creation of TMLR channels. In 12 pigs the local myocardial function (pressure-wall thickness-loops), tissue oxygen partial pressure (PO(2)), and the left ventricular intramyocardial wall pressure (IMP) was investigated simultaneously. The left ventricle was divided into 3 areas. Ischemia was induced in regions 1 and 2 by interrupting the coronary blood flow via the left anterior descending artery for 30 seconds. Region 3 served as non-ischemic control region. Thirty minutes after creation of 15-20 TMR channels in region 1, we repeated the coronary occlusion in regions 1 and 2 followed by measurement of all parameters in the 3 regions. The TMLR-treated region 1 showed a better contractility, a higher tissue PO2 and a higher intramyocardial wall pressure during the post-TMLR coronary occlusion in 8 out of 12 pigs when compared with the pre-TMLR occlusion (p<0.05), whereas the untreated region 2 continued to show severe disturbances in myocardial contractility combined with a lower tissue PO(2) and lower IMP during ischemia. Our results suggest that a blood flow via the laser channels immediately after TMLR is principally possible. However, because the channels seem to occlude in the early postoperative phase, the long-term effects of TMLR are likely to be a result of other mechanisms.     

Experimental, morphological and clinical aspects of transmyocardial laser revascularization

Experimental, pathomorphological and clinical data substantiating use of transmyocardial laser revascularisation in the treatment of coronary heart disease (CHD) are presented. It is shown that the objective criterion of clinical efficacy of transmyocardial laser revascularisation in 58 patients with CHD is an increase of myocardial perfusion due to neoangiogenesis. This leads to improvement of cardiac function and general state of the patients. Surgical intervention has no substantial influence on contractile function of left ventricular myocardium in patients with CHD.     

The role of transmyocardial laser revascularization in congestive heart failure

Transmyocardial laser revascularization (TMLR) has been approved as an indirect coronary revascularization measure through angiogenesis around created channels in patients who are not amenable to direct revascularization methods such as coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). TMLR is less invasive and there are no contraindications in terms of left ventricular function. Therefore all patients who have untreatable lesions by CABG or PTCA with reversible ischemia are candidates for TMLR therapy. In a Japanese clinical trial, improvement of left ventricular function associated with relief of persistent angina and improved perfusion was seen in 54% of patients. Significant reduction of operative risk in adjunctive TMLR (combination of TMLR with CABG) compared with isolated CABG has been also demonstrated in a randomized trial. These results indicate the usefulness of adjunctive TMLR in multivessel-disease patients with left ventricular dysfunction. Because TMLR is a simple and less-invasive technique, combined use of TMLR with off-pump CABG or MIDCAB is also an attractive revascularization strategy in ischemic cardiomyopathy patients.     

Secondary transmyocardial laser revascularization in the treatment of end-stage coronary artery disease

Transmyocardial laser revascularization (TMR) has received more acceptance within the last few years. The vast majority of TMR users report impressive clinical benefits. The underlying mechanism for benefit by TMR, however, remains somewhat unclear. Between July 1994 and September 1997, 165 patients underwent TMR at our institution. In three of our TMR patients after an initial angina-free interval of 1 to 2 years we decided to repeat the laser operation. This article focuses on the three re-TMR patients who underwent a second TMR operation 12 to 14 months after the first one. Two of the three patients are well and experience significantly less angina than preoperatively.     

Strategies for the reduction of cerebral microembolism during transmyocardial laser revascularization

BACKGROUND AND OBJECTIVES: During transmyocardial laser revascularization (TMLR), multiple microembolic signals (MES) can be detected in cerebral arteries. We sought to characterize composition and clinical relevance of these MES and to evaluate strategies to reduce cerebral microembolization during TMLR. STUDY DESIGN/MATERIALS AND METHODS: TMLR was performed in pigs. Laser energy was set to 4-10 J (group A) or 80 J (group B). Oxygen concentration was varied between 21 and 100%. MES were recorded in the ophthalmic artery. Brain and spinal cord were investigated histologically after 10 days. RESULTS: More MES could be detected during high- compared to low-energy laser procedures. Ventilation with 100% oxygen reduced the number of MES. No lesions were found on histology. CONCLUSIONS: The number of MES depends on the laser energy. Laser-induces cavitation-effects lead to an additional release of nitrogen bubbles. Thus, the microembolic load can be reduced by ventilation with 100% oxygen and by decreasing the laser energy.     

Mid-term results of combined transmyocardial laser revascularization and coronary artery bypass

BACKGROUND: Transmyocardial laser revascularization is increasingly used to treat intractable angina in the absence of graftable vessels; however, its role in combination with coronary artery bypass grafting remains undefined. The aim of this pilot study was to investigate the outcome of the combination therapy at mid-term follow-up. METHODS: Patients (n = 20) who had elective coronary artery bypass with one or more nongraftable coronary arteries were prospectively randomized to have either coronary artery bypass grafting alone or combination coronary artery bypass grafting plus transmyocardial laser revascularization with a holmium:YAG (yttrium-aluminum-garnet) laser to nongraftable areas. All patients had an exercise tolerance test preoperatively and at 6, 18, and 36 months follow-up. Stress echocardiography was performed on 17 patients at 18 months postoperatively, and regional wall motion score index was calculated in lased and nonlased nonrevascularizable myocardium of the left ventricle at rest and with dobutamine stress. RESULTS: Both groups of patients were similar in preoperative demographics and operative data. There was no perioperative death. There was no difference between the two groups in angina scoring at 6, 18, and 36 months follow-up. Exercise tolerance improved by a mean of 46.8 +/- 20.0 seconds in the coronary artery bypass grafting group versus 199.2 +/- 66.5 seconds per patient in the coronary artery bypass grafting plus transmyocardial laser revascularization group (p = 1.8 x10(-6)) at 6 months; this benefit was maintained at 18 months (157 +/- 46.3 versus 61 +/- 39.2 seconds; p = 4 x10(-4)) but was lost at 36 months (57.2. +/- 42.1 versus 68.1 +/- 46.7 seconds; p = 0.70). The mean values for wall motion score index in the lased and nonlased regions at each stage of dobutamine stress at 18 months after surgery were not statistically significant. CONCLUSIONS: The combination of coronary artery bypass and transmyocardial laser revascularization improved exercise tolerance in patients in whom complete revascularization could not be achieved by bypass grafting alone in the short term, but this benefit was lost by 36 months postoperatively. The transient improvement in exercise tolerance cannot be explained by changes in contractility in the lased areas.