British Medical Bulletin 59:249-259 (2001)
© 2001 Oxford University Press
Laser revascularisation
Treatments in ischaemic heart disease
Department of Cardiology, Papworth Hospital, Cambridge, UK
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Abstract |
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 TopFootnotes Abstract IntroductionTransmyocardial laser...Percutaneous myocardial laser...ConclusionsReferences |
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Patients who present with angina pectoris due to underlying coronary artery disease which is not controlled by medical therapy, and who have disease which is not amenable to conventional forms of revascularisation, present an increasing clinical problem. Laser techniques have been introduced to improve myocardial perfusion in this group of patients. The surgical technique of transmyocardial laser revascularisation has been evaluated in this patient population. Generally, there has been a good symptomatic response in terms of improvement in angina, and in some studies an increase in exercise capacity. The technique, however, does carry significant morbidity and mortality. More recently, a catheter-based technique has been introduced – percutaneous myocardial laser revascularisation. This technique seems to improve symptoms of angina, produce an increase in exercise capacity, with a much more favourable procedural risk profile.
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Introduction |
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TopFootnotesAbstractIntroductionTransmyocardial laser...Percutaneous myocardial laser...ConclusionsReferences |
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Effective treatment is available for the vast majority of patients with angina pectoris due to underlying coronary artery disease. The majority of patients respond adequately to medical therapy. The remaining patients usually have disease which is amenable to coronary angioplasty/stenting or coronary artery bypass surgery. There is, however, a group of patients who have severe angina despite medication, and who have coronary artery disease which is not amenable to either coronary angioplasty/stenting or coronary artery surgery. This cohort of patients is increasing in number, and they have usually had several revascularisation procedures in the past. Typically, they have diffuse disease within their coronary circulation, which particularly affects the distal part of the vessel.
The use of thoracic artery implantation many years ago1
was an attempt to provide direct myocardial perfusion. This was based on the description of a sinusoidal network in the human heart. Sen et al2 proposed the creation of transmural channels in the left ventricular wall to permit direct perfusion of ischaemic myocardium with oxygenated left ventricular blood. This concept was based on the model of the reptilian heart, in which the left ventricle is directly perfused from endothelium lined channels that radiate out from the left ventricular cavity. Mirhoseni and colleagues3 advanced the concept by using laser energy rather than mechanical energy to create the transmural channels. There has been a series of clinical trials which have evaluated transmyocardial laser revascularisation (TMR) in patients with advanced coronary artery disease. More recently, a catheter-based technique has been introduced and evaluated.
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Transmyocardial laser revascularisation |
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TopFootnotesAbstractIntroductionTransmyocardial laser...Percutaneous myocardial laser...ConclusionsReferences |
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The rationale for introducing TMR into clinical practice was based on the knowledge of a rich sinusoidal network within the left ventricular myocardium. It was hoped that the creation of laser channels would enable direct perfusion of the myocardium from within the left ventricular cavity. Although studies have demonstrated an improvement in angina in patients following TMR, the mechanism of action remains uncertain. From histological evidence, it appears that the channels close following the procedure, and it is unlikely that direct perfusion of the myocardium plays a significant role. Currently, angiogenesis seems to be the most likely explanation for the symptomatic improvement noted in this patient population. Other possible explanations include a degree of denervation as well as a placebo effect. The placebo effect, in this group of patients with ‘end stage disease’ should not be underestimated.
The procedure TMR is usually carried out under general anaesthesia using a left anterolateral thoracotomy. It is also possible to carry out the procedure less invasively using thoracoscopic techniques. The patient is investigated prior to the procedure using angiographic techniques, as well as an assessment of myocardial perfusion using either nuclear cardiology or positron emission tomography (PET). The area, or areas, to be treated by TMR are, therefore, determined beforehand using a combination of the findings from angiography and myocardial perfusion assessment. The laser probe is placed on the surface of the left ventricle, and is activated when the ventricle is maximally distended with blood. The density of the channels within each of the ischaemic zones to be treated, is usually about one every 1.0 cm2. The initial trials of TMR utilised a high energy carbon dioxide laser (The Heart Laser, PLC Medical Systems, USA), and more recently a Holmium:YAG laser system has been used (Eclipse Surgical Technologies, USA). A transoesophageal echocardiogram was used initially to demonstrate the transmural nature of the laser channel. There was a characteristic appearance within the left ventricular cavity as the laser channel penetrated the myocardium. A transoesophageal echocardiogram, however, is not now used routinely – it is clear that a transmyocardial channel has been created since bleeding occurs at the epicardial surface. This bleeding from the channels usually stops spontaneously. Sometimes, digital pressure is required to stop the bleeding, and occasionally a suture is necessary.
Clinical trials
One of the early trials of TMR was reported by Horvath et al4. This was an uncontrolled study of patients with angina which was not adequately controlled by medical therapy. The patients had evidence of reversible myocardial ischaemia, and they had coronary artery disease which was not amenable to treatment by either coronary angioplasty/stenting or coronary artery bypass grafting. The majority of patients experienced a significant improvement in terms of angina. Some 75% of patients experienced a reduction of at least two Canadian cardiovascular scores (CCS) classes in terms of their angina. The procedure, however, was not without significant risk. There was a peri-operative mortality of some 9%. The results from a registry of TMR, using a high energy CO2 laser, has been reported5. The registry included sites within Europe and Asia. In the registry report, 50% of patients demonstrated an improvement of at least two CCS angina classes, and there was an operative mortality of almost 10%.
Following on from these initial uncontrolled trials, there have been several trials of TMR, some of which have used the CO2 laser, and some the Holmium:YAG laser equipment. There have been prospective randomised trials carried out in the US6 and also in the UK7 using the high energy CO2 laser. These trials were similar in design. Following assessment, suitable patients were randomised to either continued medical therapy, or TMR plus their standard medical treatment. In both trials, there was an improvement in angina. In the US trial6, 72% of patients in the TMR group experienced an improvement in angina of at least two classes. In the control group (medication only), only 13% of patients experienced an improvement in angina of at least two classes. The symptomatic benefit noted in the UK trial7 was less impressive. In the TMR group, at 12 months only 25% of patients had an improvement of at least two angina classes, as compared with 4% of the control group. The US trial was also criticised because of a high cross-over rate from the control group (medical therapy) to the TMR group. Clearly, this made interpretation of results much more difficult. A further problem was the fact that the 12 month follow-up data were incomplete. The UK trial also assessed exercise capacity, using both treadmill exercise times as well as the 12 min walking distance. Both of these measures of exercise capacity improved slightly in the TMR group, although the difference between the TMR group and the control group was not statistically significant. In the UK trial, the peri-operative mortality was 5%. The periprocedural morbidity was significant. One-third of patients developed either a wound infection or respiratory infection which required treatment with antibiotic. Transient arrhythmia, which was usually atrial fibrillation, occurred in the peri-operative phase in some 15% of patients, and 12% of patients developed symptoms from left ventricular failure which required a transient increase in their diuretic therapy. These trials, therefore, demonstrate that whilst TMR may improve angina, and result in some increase in exercise capacity, it does carry significant morbidity and mortality.
There have also been two large studies of TMR using the Holmium:YAG laser. The ATLANTIC study8 randomised a total of 182 patients to either continued medical therapy or TMR with continued medication. In the TMR group, there was a reduction of at least two angina classes at 12 months of 61% of patients, as compared with 11% of patients in the control group. The ATLANTIC study also demonstrated an improvement in exercise capacity at 12 months follow-up. There was an improvement in exercise capacity in the TMR group of a mean of 65 s, whereas in the control group there was a mean decrease of 46 s – this difference was statistically significant. A further study of TMR using a Holmium:YAG laser was reported by Allen et al9. This randomised, prospective study involved 275 patients in 18 centres. Following assessment, 143 patients were randomised to medical therapy alone, and 132 were randomised to TMR plus continued medication. At 12 month follow-up, there was a decrease in at least two angina classes noted in 76% of the patients treated with TMR, whereas a reduction in two angina classes in the control group occurred in 32% of patients. The operative mortality in this study was 5%, and in the ATLANTIC study8 the operative mortality was 1%.
Therefore, in both the initial uncontrolled trials, as well as in the subsequent prospective randomised trials, TMR seems to produce symptomatic benefit. Usually, at least half of patients with angina and disease not suitable for conventional revascularisation techniques, experience a reduction in at least two angina classes at 12 months of follow-up. Secondly, exercise capacity has usually increased following TMR, although this has not always been a statistically significant improvement. It is clear, however, that the technique of TMR is associated with significant morbidity, as well as a peri-operative mortality of 5–10%. These results are summarised in Table 1.
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Percutaneous myocardial laser revascularisation |
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TopFootnotesAbstractIntroductionTransmyocardial laser...Percutaneous myocardial laser...ConclusionsReferences |
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In view of the morbidity and mortality associated with the surgical approach of TMR, catheter-based laser techniques have been developed. It is now possible to deliver laser energy percutaneously, using a Holmium:YAG laser introduced using a femoral artery approach. Using this technology, the laser energy is delivered to the endocardial surface of the ventricle, rather than the epicardial surface utilised with TMR. The percutaneous approach is carried out under local anaesthetic. Since there is no requirement for general anaesthesia, and since there is no requirement for a thoracotomy, the technique is much more attractive from the patient's view-point. Following TMR, patients often need to stay in hospital for up to 10 days, whereas patients can usually be discharged the following day after a percutaneous procedure.
The procedure Currently, there are two systems available to deliver Holmium:YAG laser energy to the endocardial surface of the left ventricle. The first technique, percutaneous myocardial laser revascularisation (PMR, Eclipse Surgical Technologies, USA) involves a standard radiographic technique. The second approach of direct myocardial revascularisation (DMR, Biosense, Johnson & Johnson, USA) uses an electromechanical mapping system and catheter location technology.
The Eclipse PMR system was originally developed by CardioGenesis, USA. Access to the left ventricle is gained using a 9 French sheath which is introduced into the femoral artery. There are essentially three parts to the equipment. The first is an ‘aligning catheter’, which is advanced and positioned in the left ventricular cavity. This is available in a variety of curves. The shape selected depends on the configuration of the left ventricle, as well as the area to be treated. The second part of the equipment is the ‘laser catheter’. This has a right-angled bend just before the tip. The laser catheter is advanced though the aligning catheter and rotation of the laser catheter facilitates access to the various parts of the left ventricle. The third part of the equipment is the ‘laser fibre’. This is advanced through the laser catheter, in order to make contact with the endocardial surface of the left ventricle. The manipulation and positioning of the equipment is carried out using radiographic screening. It is standard practice to use the 40° right anterior oblique projection, together with the 50° left anterior oblique projection, usually with 10° of cranial angulation. Once the views have been selected, it is important that the patient does not move during the laser procedure.
The aligning catheter is advanced into the left ventricular cavity at the start of the procedure. Following this, two left ventricular angiograms are performed – one in the right anterior oblique, and one in the left anterior oblique projections. The outline of the left ventricular angiogram is then traced onto the acetate sheets which have been fixed over the viewing screens. During the procedure, these traced outlines act as ‘maps’ of the left ventricular cavity. The patient is assessed prior to the PMR procedure by angiography, as well as an evaluation of myocardial perfusion. This may be carried out using nuclear cardiology, or alternatively PET. The findings from the angiogram and the perfusion scan indicate which area of the left ventricle requires laser therapy. By manipulating the aligning catheter, and/or the laser catheter, it is possible to access most parts of the left ventricle. The region selected for treatment may be the anterior wall, the inferior wall, the lateral wall or the septum. Once the laser catheter is orientated towards the region to be treated, the laser fibre is advanced in order to make contact with the left ventricular endocardium. This can be ‘felt’ by the operator, and can also be seen radiographically since the laser catheter is ‘pushed back’ from the endocardial surface of the left ventricle. Contact with the anterior or inferior wall of the left ventricle is best seen using the right anterior oblique projection. Contact with the lateral wall or septum of the left ventricle is usually best seen in the left anterior oblique projection.
The laser is activated once an appropriate site has been selected, and contact has been made. Activation of the laser produces a channel which is approximately 3 mm deep into the left ventricular myocardium. The laser fibre is then usually advanced slightly, and a further burst of laser energy is delivered. This results in a channel which is around 6 mm in depth. The laser fibre is then withdrawn into the laser catheter. A different site is then selected by further manipulation of the guiding catheter and/or laser catheter. Prior to the PMR procedure, the patient undergoes transthoracic echocardiography. It is important to ensure that the area to be treated is at least 8 mm in thickness – this reduces the risk of left ventricular perforation. The apex of the left ventricle is usually the thinnest part of the left ventricular wall. When treating the apex, typically only one burst of laser energy is delivered. Once the laser energy has been delivered, the site is marked in the two views on the acetate sheet. The channels are created about 1 cm apart. The map of the channels is usually best seen in the left anterior oblique projection when treating the anterior wall or the inferior wall. The right anterior oblique projection is best for mapping the channels created when treating the lateral wall or septum. Usually, 10–15 channels are created in each of the regions which have been shown to have evidence of reversible myocardial ischaemia.
Patients are anticoagulated during the PMR procedure. A bolus of 10,000 units of heparin is usually given at the start of the procedure, and the ACT is monitored throughout. During manipulation of the guiding catheter and laser catheter, ventricular arrhythmias occur commonly – this is usually ventricular premature beats, although non-sustained ventricular tachycardia can be induced. During manipulation, it is also possible to induce left bundle branch block. This does not usually have any sequelae, although it is important to position a temporary pacing wire prior to PMR if the patient has pre-existing right bundle branch block. If the patient has a thin left ventricular wall in the region to be treated, then it may be feasible to proceed with the treatment, although only one burst of laser energy being used, thereby minimising the risk of perforation. If the patient has definite evidence of left ventricular thrombus on the transthoracic echocardiogram, then PMR should not be undertaken. Access to the left ventricle may also be precluded by the presence of advanced peripheral vascular disease, or significant aortic stenosis.
The equipment used for DMR enables both electromechanical mapping of the left ventricle, as well as the delivery of laser treatment, without the need for radiographic screening. The sophisticated mapping system with DMR uses a very low energy source, together with catheter electrodes which have sensors at their tip, in order to locate the exact position of the catheter in three dimensional space. The mapping catheter is positioned at many sites on the endocardial surface of the left ventricle. The electrical and mechanical information received is then integrated. This technology is useful in determining whether the left ventricle at that site is normal, scar tissue, or ischaemic tissue. The electromechanical maps which are generated are, therefore, useful in identifying the target regions of the left ventricle to be treated by laser energy. Using the location sensors, the laser catheter can be guided towards the region to be treated. An additional application of this technology is for the delivery of other intramyocardial treatments, such as growth factors.
A triangular location pad generates an electromagnetic field, and this interfaces with a catheter which has a deflectable tip, and which contains a miniature location system. Therefore, a ‘real time’ electrical and anatomical map of the endocardial surface of the left ventricle can be created. The system also requires a stationary reference catheter, which is usually placed externally on the body surface. The information received from the mapping catheter is processed by a workstation (the NOGA unit) in order to construct the three dimensional left ventricular image.
The position of the mapping catheter is gated to the end of diastole. Its position is recorded relative to the location of the fixed reference catheter on the body surface. This compensates for both patient or cardiac motion. The mapping catheter tip is positioned at multiple sites on the endocardial surface of the left ventricle. This facilitates the three-dimensional reconstruction of the left ventricle anatomically. In addition to the mechanical activity, electrical signals are acquired from the mapping catheter , and these can be superimposed on the three-dimensional anatomical map. Regions of the left ventricle which have low electrical activity and impaired mechanical activity usually represent areas of previous myocardial infarction. A region with high electrical and mechanical activity usually represents normal myocardium. In sites where there is normal electrical activity, but impaired mechanical activity, there is typically severe ischaemia/hibernating myocardium.
The Biosense system, therefore, has many potential applications. First, the electromechanical maps which are acquired help to identify the ischaemic parts of the left ventricular myocardium, which may be targets for DMR laser treatment. Second, the navigation system may also be useful for guiding the laser catheter during the DMR procedure. The channels which have been created during laser treatment can be indicated on the electromechanical map in real time. Third, the technology may prove to be useful for the intramyocardial delivery of growth factors, or other agents.
Clinical trials
The results of a randomised prospective trial of PMR were published in November 200010. A total of 221 patients were recruited and randomised from 13 centres – 12 in the US and 1 UK site. All of the patients who were randomised had angina which persisted despite medical treatment, and they had angiographically proven coronary artery disease which was not suitable for conventional forms of revascularisation. In the trial, 111 patients were randomised to medical treatment alone, and 110 to PMR and continued medical treatment. In the PMR group, at 6 months there was a mean reduction of 1.4 CCS angina classes, compared with 0.13 in the control group (P = 0.001). In terms of treadmill exercise time at 6 months, there was a 30% increase in exercise time in the PMR group, as compared to 5% in the control group. This was statistically significant, and the baseline values were around 400 s in both of the groups. At 12 months, exercise tolerance increased by a mean of 89 s in the PMR group, compared with 12.5 s in the control group (P = 0.008; Fig. 1). Angina status was evaluated using a masked assessment. At 12 months, angina class fell by two or more classes in 34% of the PMR patients, compared with 13% of the medically treated group. There were no peri-operative deaths in the PMR group. The morbidity associated with the PMR procedure was low. Of the 110 patients who underwent PMR, one developed cardiac tamponade requiring percutaneous drainage and one patient developed atrio-ventricular block which required permanent pacing. It is clear, therefore, that the morbidity and mortality associated with PMR is vastly different to that encountered with TMR.
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The criticism of the PACIFIC trial is that it was not a ‘double blind trial’. A trial has been performed where the patients randomised to the control group underwent a ‘sham’ procedure. The laser equipment was positioned in the left ventricular cavity, but no laser energy was delivered. The results of this trial are not yet available, but are clearly awaited with interest.
In terms of clinical trials with the DMR laser system, preliminary results of a trial have been presented, but have not yet been published. The DIRECT trial involved a total of 298 patients who had angina despite medication, and who were not suitable for conventional forms of revascularisation. These patients were randomised to one of three groups. The first group, the ‘placebo’ group, received a mapping procedure only using the Biosense equipment, the second group underwent ‘low dose laser therapy’ (10–15 laser channels per treatment zone) and the third group had ‘high dose laser therapy’ (20–25 laser channels per treatment zone). In the DIRECT trial, the patient was blinded to their treatment group. At 6 months' follow-up, there was an increase in treadmill exercise time of 7–10%, but there was no significant difference between the three groups. The baseline exercise time was 360–390 s. At 6 months, there was also an improvement in angina class in all three groups, but again there was no significant difference between the groups. It was suggested by the presenters of the preliminary results from the DIRECT trial that the changes demonstrated in symptoms and exercise capacity were due to the placebo effect. It is interesting to note that the improvement in exercise duration on treadmill testing in the DIRECT trial (
10%) was much lower than that found in the PACIFIC trial (30%). As outlined above, there are substantial differences in the techniques utilised for PMR and DMR, and these may account for some of the differences in the findings from clinical trials. First, the technique for selecting the region to treat is quite different with PMR and DMR. With PMR, the angiogram and perfusion scan are used, whereas with DMR there is an influence from the electromechanical map which is generated at the start of the procedure. Second, the amount of energy delivered is different between PMR and DMR, and this affects the depth of the channels created – there is greater penetration with the PMR technique than with DMR. Finally, with the PMR technique it is extremely clear when contact has been made with the endocardial surface of the left ventricle. With the DMR technology, contact with the endocardial surface prior to laser therapy delivery, is less certain.
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Conclusions |
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TopFootnotesAbstractIntroductionTransmyocardial laser...Percutaneous myocardial laser...ConclusionsReferences |
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We look forwards to reviewing the results of the DIRECT trial when published. The findings of the PMR trial in which the control group underwent a ‘sham’ procedure are also awaited with interest. If the future trials of catheter-based laser therapy confirm a beneficial effect, then it is likely that the percutaneous approach will be preferred. It is clear from the results of clinical trials to date that PMR carries a much lower morbidity and mortality than TMR. This may not necessarily, however, be ‘the end of the road’ for TMR treatment. It may still have a role as an adjunct to coronary artery bypass surgery. There are many patients undergoing coronary artery bypass surgery who have some vessels suitable for grafting, and other vessels which are not. In this patient group, a hybrid approach has been used. The vessels suitable for surgery are grafted, whereas the regions supplied by vessels which are not suitable for surgery are treated by TMR. Several centres continue to carry out these combined procedures.
If the future trials confirm the benefits demonstrated in the PACIFIC study, then it is likely that PMR will continue to be used in patients with angina and coronary artery disease which is not suitable for conventional forms of revascularisation. Indeed, its use would continue to increase. There may also be a role for hybrid procedures using percutaneous coronary intervention. Patients would undergo angioplasty/stenting to lesions that were amenable to this form of treatment. The areas of myocardium supplied by vessels which were diffusely diseased, and not suitable for conventional revascularisation may be amenable to treatment by PMR.
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Footnotes |
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TopFootnotesAbstractIntroductionTransmyocardial laser...Percutaneous myocardial laser...ConclusionsReferences |
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Correspondence to: Dr P M Schofield, Consultant Cardiologist, Papworth Hospital, Papworth Everard, Cambridge CB3 8RE, UK
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References |
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TopFootnotesAbstractIntroductionTransmyocardial laser...Percutaneous myocardial laser...ConclusionsReferences |
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