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LASER PERCUTANEOUS MYOCARDIAL REVASCULARISATION : A TREATMENT IN GENESIS

Robert J Whitbourn
Director of Coronary Care, St. Vincent’s Hospital Melbourne, 41 Victoria Parade, Melbourne, Victoria - 3065, Australia.


In patients with coronary artery disease, improvements in myocardial perfusion have traditionally been achieved by increasing blood flow through the existing coronary vessels. In contrast, laser myocardial revascularisation techniques uses laser energy to create new myocardial channels and produce effects which lead to improved myocardial perfusion and reduction in angina.

Laser transmyocardial revascularisation (TMR) requires thoracotomy in order to gain access of the laser to the epicardial surface of the heart. Percutaneous myocardial revascularization (PMR), utilizes transmission of laser energy to the endocardial surface of the left ventricle along a flexible, fiberoptic catheter, via a femoral arterial approach.

Laser-tissue interactions depend on the energy used and its means of delivery. Thermal, mechanical and chemical effects of laser channel creation may all impact on the myocardium. Stimulation of angiogenic growth factors, with consequent neovascularization, appears to be the principal mechanism responsible for the clinical effects of this innovative therapy.

Patients with severe, chronic angina, refractory to drug therapies, and not suitable for traditional surgical or percutaneous revascularisation approaches may be candidates for TMR or PMR techniques. Clinical studies of TMR have found reductions angina class, hospital admissions and the number of myocardial perfusion defects, but at the cost of morbidity and mortality related to the attendant surgical approach. Clinical studies of PMR have reported improvements in angina class, exercise duration and trends to improvement in radionuclide perfusion defects. The first randomized trial of PMR - the PACIFIC study - has shown the percutaneous approach to be safe and well tolerated and may provide insight into the future clinical role of laser percutaneous myocardial revascularization.

INTRODUCTION

In patients with coronary artery disease, strategies for improving myocardial perfusion have traditionally applied techniques to restore blood flow through the existing coronary circulation. Laser myocardial revascularisation techniques, on the other hand, are based on the premise that creating new myocardial channels, bring about biological and mechanical effects that increase perfusion to ischaemic areas.

Wearns et al first suggested that blood may actively flow from the ventricle into the vasculature of the myocardium. [1] In the 1960’s, Sen described myocardial perfusion directly from the ventricular cavity via a network of channels in reptilian hearts and later demonstrated that creating new channels using "myocardial acupuncture", protected canine hearts from the effects of ligation of the left anterior descending artery. [2]

Later, Mihroseini used a CO2 laser to create transmyocardial channels from the epicardial surface of the canine heart. [3, 4] Production of transmyocardial channels using a CO2 laser was first performed in humans as an adjunct to coronary bypass graft surgery in a series of 12 patients unable to be completely revascularised by conventional techniques.
[5, 6, 7] The constraints of CO2 lasers require an open thoracotomy to deliver the energy to the epicardial surface and hence, thissystem carries the morbidity of such a surgical approach.

In contrast, Holmium:aluminum-yttrium-garnet (Ho:YAG) laser energy can be transmitted along an optical fiber, allowing creation of channels from the endocardial surface of the left ventricle. This technique is known as percutaneous myocardial revascularization (PMR). A fibreoptic catheter is passed via a femoral artery approach, retrogradely across the aortic valve into the left ventricle, where energy is delivered to the endocardial surface to create channels into the targeted area of myocardium. Hence, PMR generates new myocardial channels, without the need for surgical access. Animal studies first demonstrated that the PMR technique was possible and this led to the clinical investigation of its use. [8]

PATIENT SUITABILITY FOR TMR OR PMR

Patients to be considered suitable for PMR should have definite, severe angina, unable to be treated by other means. Laser revascularisation therapies are proposed to ameliorate anginal symptoms and have not been purported to confer mortality benefit. Patients with diffuse coronary disease, small target vessels, chronic total occlusions and reversible myocardial ischaemia and where traditional revascularisation strategies are not possible may be suitable candidates for PMR. To define a target area for channel creation, a site of reversible myocardial ischaemia should be determined by stress nuclear or echocardiographic scans. Determination of left ventricular function and wall thickness in the targeted area by echocardiography may be necessary for PMR procedures, so as to avoid perforation during the procedure. Contra-indications to laser PMR are shown in Table 1.

MECHANISMS OF ACTION

Laser channel creation appears to produce acombination of thermal, mechanical and chemical effects, which bring about tissue changes.

Table 1
PMR : Contraindications
Significant aortic stenosis
Peripheral vascular disease precluding a femoral approach
Absence of reversible ischaemic defect
LV wall thickness < 8 mm, thinned or scarred wall in target area
Poor LV function (EF < 30%)
Absence of angina symptoms

The denervation hypothesis, for example, suggests that during laser channel creation, heat dispersion along myocardial neurovascular bundles results in local denervation. [9] This more likely occurs with TMR, where the laser energy is applied epicardially, in closer proximity to the neurovascular bundles. Other hypotheses include thermo-ablation with necrosis of myocardial tissue and the placebo effect.

The original theory underlying PMR was that blood might flow into newly created conduits, directly from the left ventricle. If this was the predominant means of improved myocardial perfusion, then benefit should be immediate and parallel channel patency. However, laser myocardial channels may not salvage acutely ischaemic myocardium and results have been conflicting with respect to their long-term patency. [3, 5, 10-13]

Histological studies have demonstrated endothelialisation and an increase in small capillaries in the lased areas. [14-18] Current consensus is that angiogenesis occurs after stimulation of angiogenic growth factors in response to laser-induced cellular trauma and appears to be the principal underlying mechanism. [19] This contention is supported by clinical reports of continuing improvement in symptoms and tests of myocardial perfusion, with time. [6, 7, 20-24]

Tissue responses to lasers are largely dependent upon the energy produced and the mode of delivery. [25] Holmium:aluminum - yttrium - garnet(Ho:YAG) lasers in clinical use deliver 2 Joules of energy per pulse and produce thermal trauma and tissue cavitation due to acoustic effects, which result in a zone of injury around myocardial channels. [26]

Table 2
PMR : Possible mechanisms of action
Flow through patent channels
Placebo effect
Myocardial infarction
Denervation
Angiogenesis

CLINICAL STUDIES

The earliest clinical use of TMR as an adjunct to coronary bypass graft surgery in a series of 12 patients, demonstrated relative safety and reported a reduction in angina and a beneficial effect on myocardial perfusion in the laser-treated areas. [5, 6, 7] Cooley et al later reported twelve month follow-up after TMR as sole therapy in a series of 21 patients with angina refractory to normal therapy. They described a significant reduction in angina class 3.7 + 0.4 vs 1.8 + 0.6 (p < 0.01) and an increase in mean subendocardial/ subepicardial perfusion ratio in treated vs untreated areas (20% + 9% vs 2% + 5% p < 0.001). [21] Recently, a multicentre trial of TMR as sole therapy in 200 patients with angina refractory to medical therapy and contraindications to PTCA or CABG, was reported. The perioperative mortality was 9% and angina class decreased significantly from before treatment to class at 3, 6 and 12 months (p < 0.01). In addition, there were significant decreases in the number of admissions for angina and the number of myocardial perfusion defects in the treated areas.[22]

In a series of 12 TMR treated patients, dobutamine stress echocardiography showed a significant reduction in ischaemic segments, (64% to 20% p=0.005) and an increase in normal myocardial segments (7% to 33% p=0.004), at 3months. [24] Preliminary results of a randomized trial of TMR vs medical management showed a reduction CCS angina class II or better in 85% of TMR patients vs 18% of medically treated patients at 6 months (p < 0.0001). Results were sustained with TMR patients having CCS angina class II or better being 81% at 12 months. [27]

Results of a feasibility study of PMR for use in severe angina pectoris have demonstrated the method to be technically possible and relatively safe. [28] Pilot studies using the PMR systems have reported improvements in angina class from an average of CCS of 3.4 to 1.6 and with exercise duration increased from 300 seconds to 485 seconds (p=0.01). Trends to improvement in reversible thallium defects after PMR also appear encouraging. [23]

The recently reported results from the PACIFIC study, a randomised trial of PMR versus medical therapy alone, showed that 46% of PMR patients had at least a 2 class angina improvement at 6 months, compared with only 6% of those non PMR treated patients. There was a clinically and statistically significant average reduction in angina class for the PMR treated group compared to the medication alone treated group (-1.4 vs -0.25, p < 0.00001). [29] In addition, there was a significant improvement in exercise tolerance at 3 and 6 months. The laser PMR procedure was well tolerated with minimal periprocedural complications reported.

DISCUSSION

 Laser percutaneous myocardial revascularisation PMR is an innovative means of improving symptoms, exercise tolerance and quality of life in those patients with severe angina unable to be treated by other methods of revascularisation.

Transmyocardial revascularisation (TMR) has been shown to reduce angina class and decrease hospitalisation rate, though mortality benefit has not been reported. It appears that ischaemic myocardial tissue responds to laser injury byaugmenting new small vessel growth, with the process likely mediated local stimulation of growth factor production.

 With angiogenesis within the myocardium being the principal response, there would appear to be no specific advantage to the creation of laser channels from the epicardial surface compared to the endocardial surface of the left ventricle. The technique of PMR utilises this concept that tissue responses to laser energy are independent of the myocardial surface to which it is delivered. By delivering Holmium: YAG laser energy percutaneously via a fibreoptic catheter, stimulation of neovascularisation can be initiated without the need for thoracotomy.

 With the latest reports outlining safety and significant improvements in angina, laser PMR may become a therapy for use either alone or as an adjunct to PTCA, to improve perfusion to those areas unable to adequately treated by other means.

Recently, the concept of integrating laser PMR with a system to deliver either angiogenic growth factors such as vascular endothelial growth factor (VEGF), or genes that encode local production of stimulatory factors, has been proposed. Revascularisation strategies of the future may involve a combined approach using the thermo-ablative properties of the laser PMR technique coupled with local delivery of angiogenic agents to maximally stimulate myocardial neovascularisation.

CONCLUSIONS

Percutaneous laser myocardial revascularization is feasible, relatively safe and improves exercise duration and clinical angina grade in suitable patients. Ongoing randomized trials are in progress and hope to confirm clinical efficacy long term and to demonstrate improvements in reversible myocardial perfusion defects.

REFERENCES

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