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.     

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 myocardial function after transmyocardial laser revascularization according to cine magnetic resonance in a porcine model

OBJECTIVE: This study was undertaken to demonstrate that transmyocardial laser revascularization of hypoperfused myocardium improves regional and global myocardial function. METHODS: Cine magnetic resonance imaging was used to monitor regional wall thickening (in millimeters) and cardiac output (in milliliters per kilogram per minute). Cine magnetic resonance imaging was performed before and 8 weeks after transmyocardial laser revascularization was applied to the hypoperfused lateral wall of the left ventricle (target area) in a porcine model (n = 9, transmyocardial laser revascularization group). A second group of animals was left untreated (n = 8, control group). RESULTS: Regional wall thickening in the target area improved after transmyocardial laser revascularization (0.7 +/- 0.3 mm to 3.7 +/- 1.9 mm, P <.02) and was significantly higher (P <.01) after transmyocardial laser revascularization than in the control group, in which it did not improve (0.5 +/- 0.6 mm to 0.5 +/- 1.2 mm). Accordingly, cardiac output and microsphere-derived myocardial blood flows were significantly higher than in the control group (P <.01), and the amount of triphenyltetrazolium chloride-stained myocardium was lower (P <.01). CONCLUSION: Cine magnetic resonance imaging demonstrates improved global and regional myocardial function after transmyocardial laser revascularization in a porcine model.     

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.     

Factors influencing results and outcome after transmyocardial laser revascularization

Background. Transmyocardial laser revascularization (TMR) has been increasingly used during the recent past for patients with diffuse coronary artery disease. Because this operation is associated with significant morbidity and mortality, it is important to select patients for TMR who are likely to benefit from the procedure.

Methods. We performed an univariate logistic regression analysis of 20 factors on the benefits and outcomes of 134 patients who underwent isolated TMR at our institution between November 1994 and May 2000.

Results. Responders and nonresponders differed significantly with regard to the incidence of diabetes mellitus. For diabetic patients the chance of profiting from the TMR operation was only 43% of that of nondiabetic patients (odds ratio = 0.43 [0.20 to 0.92]). Furthermore, patients with a preoperative body mass index of less than 25 had a threefold increase in the probability of death during the first year after TMR as compared to patients whose body mass index was 25 or more (odds ratio = 2.97 [1.05 to 8.40]). The incidence of diabetes was also slightly but not significantly different between 1-year survivors and nonsurvivors.

Conclusions. In diabetic patients we recommend caution in selecting therapeutic TMR because outcomes are less satisfactory than in nondiabetics. Furthermore, patients with a body mass index below 25 have a significantly higher risk for death during the first postoperative year. Studies based on larger patient populations should follow.     

Improved quality of life after XeCl excimer transmyocardial laser revascularization: results of a randomized trial

BACKGROUND AND OBJECTIVES: We assessed quality of life (QOL) after XeCl transmyocardial laser revascularization (TMLR). STUDY DESIGN/MATERIALS AND METHODS: Thirty patients were randomized to receive XeCl excimer TMLR or optimal cardiac medication (controls). QOL was assessed at baseline, 1, 3, 6, and 12 months using three different questionnaires: The Medical Outcomes Study Short Form-24 (MOS SF-24), the EuroQol Standardized Questionnaire, and the Seattle Angina Questionnaire (SAQ). The primary outcome measure was the change in score between baseline and 12 months. RESULTS: TMLR patients scored significantly better compared to controls in the MOS SF-24 social functioning, energy, general health, and bodily pain domains, in the EuroQol usual activity domain and the EuroQol Visual Analogue Scale, and in the SAQ physical limitation, angina frequency and disease perception domains. CONCLUSIONS: QOL significantly improved after XeCl excimer TMLR compared to medication. These results are similar to reported improvements in QOL after CO(2) and Ho:YAG TMLR.     

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.     

Inflammatory response and angiogenesis after percutaneous transmyocardial laser revascularization

BACKGROUND: The aim of our study was to investigate the inflammatory response immediately after percutaneous transmyocardial laser revascularization (PTMR) along with the underlying mechanism of angiogenesis. METHODS: Patients with angina pectoris underwent coronary angiography and were divided into two groups. Group A (n = 10) included patients with obstructed vessels who received PTMR, whereas group B (n = 5) comprised patients who had normal coronary arteries. Blood levels of neutrophils, procalcitonin, troponin-I, myoglobin, and creatine kinase (CK) mass were evaluated in each patient before angiography and monitored up to 48 hours after the procedure. Six patients were injected with 99mTc-leukoscan approximately 60 to 90 minutes after PTMR. During the 240 to 300 minutes after the radionuclide administration, single photon emission tomography (SPET) was performed and compared with conventional 99mTc-sestamibi-SPET. RESULTS: A significant increase in blood levels of neutrophils and procalcitonin was observed in group A only (p < 0.005). A slight but significant increase of troponin-I was evident in the same group (p < 0.05), and a distinct myocardial uptake of 99mTc-Leukoscan-SPET was observed in each patient along homologous regions treated by PTMR. CONCLUSIONS: The increased amount of neutrophils (both circulating and inside the treated myocardial areas) along with the raised levels of procalcitonin were the immediate reactions to PTMR. This systemic and intramyocardial inflammatory response is the underlying mechanism that gives rise to angiogenesis.     

激光心肌打孔血运重建术的临床应用

作者对７例不能作冠状动脉搭桥和经皮冠状动脉球囊扩张、并且药物治疗无效的冠心病心绞痛患者使用国产７００瓦ＣＯ２激光器作激光心肌打孔血运重建术。７例患者心肌打孔数目１６２个,平均２４个。手术时间１５０±３０分。１例于术后第３天因呼吸衰竭死亡,其余６例术后随访２～１２个月。随访包括心绞痛级别、用药情况及心功能,并在术后３、６和１２个月检查超声心动图和心肌ＳＰＥＣＴ。结果显示：４例心绞痛消失,２例明显缓解。２例于打孔后１～６个月作平板运动试验,运动时间比术前延长,４例做超声心动图示静息状态下室壁动度均有增加,１例在术后１２个月左室射血分数由术前的４２％提高到５４％;２例做超声心动图－多巴酚丁胺检查示多巴酚丁胺对心室壁动度的作用及心肌对多巴酚丁胺的最大耐受量均比术前增强;心肌ＳＰＥＣＴ示与术前比心肌打孔区的血液灌注明显增加。作者认为：本方法作为冠心病治疗的一种新方法,可有效地缓解心绞痛,改善心肌血液灌注,提高心脏功能。     

Acute and chronic effects of transmyocardial laser revascularization in the nonischemic pig myocardium by using three laser systems

BACKGROUND AND OBJECTIVE: Transmyocardial laser revascularization (TMLR) improves symptoms in patients with coronary heart disease. It is based on the hypothesis of direct perfusion of ischemic myocardium by means of laser-created channels. Three different lasers were used to study alternative effects on myocardium. STUDY DESIGN/MATERIALS AND METHODS: The present study was conducted to evaluate comprehensively and compare the short and long-term tissue effects and the basic interaction mechanisms of CO2, Ho:YAG, and Er:YAG laser radiation with myocardium. The dynamics of laser-induced impacts in gel used as tissue phantom was visualized by time-resolved flash photography. Pressure measurements performed during perforation of myocardium in vitro revealed the explosive character of the ablation process. Channels made into the left ventricle of normal pig hearts were examined immediately and 6 weeks after creation. RESULTS: Regardless of laser source, all channels became occluded within 6 weeks by scar. Minimal acute thermal damage by Er:YAG laser corresponded to smaller scars. Pulsed Ho:YAG caused stronger tissue tearing than continuous wave CO2 irradiation. An increased volume density of intramyocardial vessels was found about the scars 6 weeks after treatment with all lasers. CONCLUSION: The laser sources permitted to study outcome of pressure effects and thermal damage in vivo. There were only minor differences between the three laser systems used. Rapid channel occlusion suggests that rather than revascularization, subsidiary physiologic tissue effects elicited by the thermal, oxidative, or mechanical action of the laser impact may contribute to the beneficial clinical effects of TMLR.     

Regional cardiac sympathetic innervation early and late after transmyocardial laser revascularization

BACKGROUND: Prior experimental and clinical studies have drawn disparate conclusions regarding the effects of transmyocardial laser revascularization (TMR) on regional cardiac innervation in the treated regions. Regional afferent denervation has been proposed as a potential mechanism of action of the procedure, although this as yet remains unproven. The purpose of the present study was to evaluate regional myocardial sympathetic innervation both early (3 days) and late (6 months) after TMR. METHODS: Mini-swine in the early group were randomized to be sacrificed 3 days after holmium:YAG TMR (n = 5) or sham thoractomy (n = 3). In the late group, mini-swine with hibernating myocardium in the left circumflex (LCx) region were randomized to sham redo-thoracotomy (n = 5), TMR of the LCx distribution with a carbon dioxide (n = 5), holmium:YAG (n = 5), or excimer (n = 5) laser. Six months postoperatively the animals were sacrificed. Additional animals in both the early (n = 2) and late (n = 2) groups served as age- and weight-matched normal controls. Immunohistochemistry and Western blot analysis for tyrosine hydroxylase (TYR-OH), a neural-specific enzyme found in sympathetic efferent nerves and a commonly used anatomic marker of regional innervation, were performed on lased and nonlased LCx and septal regions. RESULTS: Immunohistochemical staining for TYR-OH was markedly diminished in the lased myocardial regions 3 days after TMR. This staining was significantly reduced compared to untreated septal regions, sham-operated, and normal LCx myocardium. Quantitative immunoblotting confirmed a significant reduction in TYR-OH (p < 0.05) protein concentration in the lased regions 3 days after TMR. On the contrary, TYR-OH staining was present in LCx myocardium surrounding the laser channels of all animals in all groups 6 months postoperatively. Staining was not different from controls. Similarly, there was no difference in LCx TYR-OH protein concentration between the normal, sham, or 6 months postoperative lased groups (p > 0.2 by one-way ANOVA). CONCLUSIONS: TMR-treated myocardium demonstrates anatomic evidence of regional sympathetic denervation 3 days postoperatively, although myocardium lased with each of the three lasers currently in clinical use is reinnervated by 6 months as evidenced by immunoblotting and immunohistochemistry for TYR-OH. These results suggest that mechanisms other than denervation may account for the long-term reductions in angina seen after TMR.     

Improved cell survival in infarcted myocardium using a novel combination transmyocardial laser and cell delivery system

Stem cell therapy has been used to treat ischemic cardiac disease with promising early results. However, there has been limited success using cell therapy in infarcted tissue. The cells have an inadequate microvascular environment in order to survive once implanted into scar tissue. The goal of this study was to create a microvascular environment into infarcted myocardial tissue using transmyocardial laser revascularization (TMR) as a pretreatment before cell implantation and evaluate cell survival afterwards. Balloon occlusion catheter-based myocardial infarct of the circumflex artery was created in a porcine model. The infarct was allowed to mature for 2 weeks. Three groups consisting of TMR alone (TMR), TMR + fluorescent-labeled allogeneic mesenchymal stem cells (MSCs) (TMR + Cells), and MSCs alone (Cells) were injected into the infarcted tissue using a combination TMR and cell delivery system (Phoenix, Cardiogenesis). The hearts were explanted at 1 week after treatment for cell and tissue evaluation. The myocardial infarcts were verified in all animals using both ultrasound and direct visual imaging. All arms of the study were successful with a mean of 2.0 +/- 10(6) MSCs injected per site into the scar tissue. All animals survived to explant at 1 week. On histological examination, 300 high-power fields were evaluated demonstrating that the TMR + Cells group had 25 +/- 5 cells and the Cells group 5 +/- 2 cells compared to baseline TMR alone by fluorescence. The use of TMR as a pretreatment for MSC injection increases early cell survival in infarcted tissue without increased adverse events. Further long-term functional and differentiation analysis will be required to evaluate the efficacy for future clinical translation.     

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.     

Survival after transmyocardial laser revascularization in relation to nonlasered perfused myocardial zones

BACKGROUND: Transmyocardial laser revascularization for severe diffuse coronary artery disease reduces angina significantly. The effect on survival, however, is questionable, and risk factors are not adequately addressed. Considering that transmyocardial laser revascularization channels do not remain patent for improving direct myocardial blood supply, other variables such as perfusion through open native or grafted vessels in remote non-transmyocardial laser revascularization areas are probably more important for survival. This hypothesis is the subject of the study. METHODS: Transmyocardial laser revascularization was performed with a CO2 laser system in 63 patients between October 1995 and December 1997. Patients received transmyocardial laser revascularization alone or in combination with coronary artery bypass grafting. The heart was divided into three perfusion zones as determined by the three major coronary arteries. Patients were divided into three groups according to the number of zones that were perfused by either a native coronary artery or a patent bypass graft: group 1 (n = 9), none; group 2 (n = 24), one; and group 3 (n = 30), two. Follow-up was performed at 3, 6, 12, 24, and 36 months and was 100% complete. Mean latest follow-up was 26.2 months, minimal follow-up of survivors was at least 12 months. RESULTS: Overall mortality was remarkably higher in group 1 (77.8%) compared with group 2 (20.8%, p = 0.005) and group 3 (13.3%, p = 0.001). Hospital mortality was 22.2% in group 1, 0% in group 2, and 3.3% in group 3. Late mortality was also higher in group 1 (55.5% versus 20.8%, and versus 9.9%, respectively). Cardiac deaths were more frequent in group 1 (55.5% versus 12.5% in group 2, p = 0.02, and versus 9.9% in group 3, p = 0.009). The number of perfused myocardial zones showed a significant influence for survival (p = 0.002). CONCLUSIONS: These data give some directional evidence that survival seems to be beneficially affected by the number of nonlasered perfused myocardial zones through native vessels or grafts in patients undergoing transmyocardial laser revascularization.     

Quality of life and survival after transmyocardial laser revascularization with the holmium:YAG laser

BACKGROUND: The purpose of this investigation was to assess postoperative survival and quality of life with transmyocardial laser revascularization (TMR) in high-risk patients. METHODS: During a 24-month period, 81 consecutive patients underwent either sole therapy TMR (n = 34) or TMR with coronary artery bypass grafting (n = 47) using a holmium:yttrium-aluminum-garnet (YAG) laser. Outcomes were assessed in three high-risk groups, including patients with left ventricular dysfunction (ejection fraction < or = 0.40) (n = 37), unstable angina (n = 30), and congestive heart failure (n = 33). Disease-specific quality of life was assessed using the Seattle Angina Questionnaire in 58 late survivors and compared with an age-matched cohort undergoing coronary artery bypass grafting only (no TMR) (n = 20). RESULTS: Overall mortality was 6% +/- 3% (+/- 70% confidence limit) and appeared higher with left ventricular dysfunction (11% +/- 5% vs 2% +/- 2%), but the difference did not reach statistical significance (p = 0.17; power = 0.16). There was also no statistical difference with unstable angina (10% +/- 6% vs 4% +/- 3%; p > 0.53) or congestive failure (9% +/- 5% vs 4% +/- 3%; p > 0.66). However, survival at 18 months was significantly lower with left ventricular dysfunction (62% +/- 9% vs 90% +/- 5%; p < 0.003) and congestive failure (48% +/- 10% vs 96% +/- 3%; p < 0.001). For sole therapy TMR, quality of life was diminished comparing TMR with coronary artery bypass grafting (p < 0.004) and coronary artery bypass grafting only (p < 0.002). CONCLUSIONS: Transmyocardial laser revascularization can be performed in high-risk patients, but survival is significantly impaired in patients with left ventricular dysfunction and congestive failure, and quality of life is diminished without some degree of direct revascularization.     

Quantification of microembolic signals during transmyocardial laser revascularization

Transmyocardial laser revascularization (TMLR) is known to induce cerebral microembolic signals (MES). We quantified laser induced MES in patients undergoing TMLR during cardiopulmonary bypass for coronary artery bypass grafting (group A) and during TMLR treatment alone (group B). The total number of MES during a single laser application with identical energy was significantly higher in group A compared to group B (P<0.001). Also the peak of MES occurred significantly later in group A (P<0.0001). An increase of laser energy was associated with an increase in numbers of MES particular in group B (r=0.641). Different TMLR modalities generate different amounts of cerebral microembolic signals. Thus, adjustment of TMLR to these modalities may reduce potentially harmful cerebral microemboli and warrants further evaluation.