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Chronic Refractory Angina |
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Laser therapyIntroductionTransmyocardial laser revascularisation (TMLR) was devised as a method of directly perfusing the myocardium with oxygenated blood from the left ventricle(1 2). This is based on the reptilian circulation, where there are no epicardial coronary arteries, just intramyocardial sinusoids that directly connect the ventricle, arteries and vein(3,4) Myocardial acupuncture had been tried previously(5) as had other techniques of increasing transmyocardial blood flow such as creating endocardial incisions6 rather than bypassing the coronary circulation. TMLR is often performed in conjunction with conventional coronary bypass surgery, but the first reported case of laser therapy alone, was in a 55 year old man with severe angina, who is still alive 12 years later(7). Initially the FDA advisory panel rejected TMLR as a therapy, however conditional approval was granted in the spring of 1998(8). Transmyocardial laser surgeryTMLR is mainly performed via a thoracotomy through the fifth or sixth intercostal space, although it can be done via a thoracoscopic approach(9). The patient is intubated and a TOE probe can be utilised as penetration of the laser into the left ventricle causes a steam like picture on echocardiography. If the patient is having a thoracotomy, then a high thoracic epidural (T4/5-T5/6) is often used to minimise pain. The pericardium is opened and transmyocardial channels are created from the epicardium to the endocardium, mainly in the ischaemic areas obviously avoiding any previous grafts. Approximately 20-40 channels are made which are 1mm in diameter and a single channel is made every square centimetre. Bleeding from the channels can usually be stopped by gentle digital pressure, or occasionally a stitch. Types of laserAt present two sorts of laser are under evaluation in the treatment of refractory angina; CO2 and the holmium:yttrium-aluminium garnet (YAG) laser. Animal experimentation has demonstrated similar histological effects after 6 weeks, but with initially increased thermoacoustic damage using the YAG laser.10 Interestingly, recent work in normal sheep myocardium looked at channels created with CO2 laser or a power drill and found that there was no histological difference.11 They postulated that the channels created resulted in a nonspecific response to injury i.e. capillaries become permeable to serum and blood elements and neutrophils then produce chemotactic factors and attract macrophages, which promote healing. Mechanism of action of TMLRThis is still uncertain. Several theories have been postulated,12 which include a placebo effect, laser destruction of sympathetic nerve endings resulting in a form of sympathectomy,13 perfusion of myocardial sinusoids directly by ventricular blood (as in the reptilian circulation), or an improvement in myocardial perfusion secondary to angiogenesis. Animal experimentation has produced different results depending on both the group involved and the animal model used; the latter can be explained in part by differing amounts of collateral circulation between species(14,15) Also various experiments have looked at the either the acute or chronic effects and both normal or ischaemic myocardium(16,17) There is a case report of patent channels in a patient who died three months after TMLR, but this is the only one.18 Most post-mortem studies have not demonstrated any patent channels, but granulation and scar tissue (19,20,21) Some PET and SPECT studies in a small number of patients post TMLR have shown a significant increase in myocardial perfusion, particularly in the subendocardial region12 (22), but this is not a consistent finding(9,23). Similarly there has been demonstrable improvement in left ventricular wall motion abnormalities on dobutamine stress echocardiography in some studies(24), but not in others(23). It should not be forgotten however, that pain relief can be obtained for several months with a high-thoracic epidural, which is often used for post-operative analgesia after thoracotomy(25). Long-term follow-up studies in chronic refractory anginaMost studies demonstrate a perioperative mortality of 5-12% (12, 23, 26) Decreases in the number of hospital admissions(9, 12) improvement in angina status (9, 12, 20, 23) and a reduction in the amount of GTN used is documented at up to 6 months(9). Significant benefits at one year was demonstrated by Gassler et al in the 22 out of 55 patients who completed this length of follow-up(20), Cooley et al in the 13 out of 21 patients(22) and by Horvath in 70 out of 95 patients(12). Nagele et al26 found a mortality rate of 23% at one year, rising to 30% at 3 years. Patients were more likely to do worse if they had an ejection fraction of <40%. At the end of a year, 35/200 patients had died in Horvath's series(12). More recently Schofield and colleagues reported on the MRC randomised trial of TMLR in patients with refractory angina(27). Although 25% of the treated group improved significantly compared to the untreated group (4%), there was a 5% perioperative mortality. They concluded that TMLR should not be advocated in this group of patients. This is at variance with the recommendations by two groups who recently completed randomised trials(28,29) In both studies the laser treated group were clinically significantly better off than the untreated patients. There was significant cross-over from ther untreated group which indicates that both the researchers and patients had high expectations of the therapy. Allen et al., make it clear that that the possibility of crossing-over to TMLR was offered as an incentive during recruitment. Unfortunately none of other researchers publish details of the recruitment process and one is left to guess at how positively the physicians presented the case for laser. Positive expectation is the main predictor of a positive placebo effect whilst negative expectations have the reverse effect, referred to as the nocebo effect. The unblinded nature of all the published studies means that the results might simply reflect a placebo effect of laser compared to the nocebo effect of randomisation to contimued treatment failure. TMLR in unstable anginaThere have been two large studies by the same investigators involving a total of 127 unstable patients(30,31). Both quoted a perioperative mortality of 12%. Allen et al(28) followed patients for 6 months and found a significant improvement in angina status. Dowling et al31 also demonstrated improvement in 42 of the surviving 57 patients at one year, however there was a total mortality rate of 22.4% in the first year. It is suggested that TMLR should be used with caution in this subset of patients. Adjunctive TMLRMinimally invasive coronary surgery is becoming a popular technique in patients who would have a high complication risk if they went on cardiopulmonary bypass. TMLR can be used as an adjunct to hopefully revascularise patients more completely. Trehan et al(32) reported on 77 patients who underwent a combined procedure. There was one perioperative death and 14 of the 16 patients who completed 12 months of follow-up were painfree. A randomised controlled trial is required to confirm the additional benefit of adjunctive TMR. Possible future uses of TMLRIn experiments on pigs, TMLR has been demonstrated to improve transfection efficiency of DNA encoding for vascular endothelial growth factor(33). These investigators felt that this combination could work together to improve collateral circulation. If Laser failsSummaryTransmyocardial laser revascularisation is expensive, with a high but improving perioperative mortality. There have been many case reports of lasting benefits yet there does appear to be a fall off in efficacy after a year. In most studies to date, patients tend to have been followed for about a year hence longer-term gains have yet to be determined. It is impossible to judge how large a component the placebo effect plays, as symptomatic benefits do not always correlate with objective findings. The mechanism of action of TMLR is not clearly defined and there is no consensus available from either animal or human studies about its exact effects on myocardial perfusion and left ventricular function. References
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