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Ann Thorac Surg 1999;68:468-469
© 1999 The Society of Thoracic Surgeons
e-mail: pwhittaker{at}dnamail.com
Invited commentary
Clinical application of transmyocardial revascularization (TMR) has resulted in the consistent finding of significant and prolonged reductions in angina, no matter what device was used. However, this clinical success is still in search of a mechanism. The original premise, the "de-evolution" of mammalian hearts to resemble the highly trabeculated and sinusoidal cardiac structure of reptiles by the creation of multiple channels, has been discounted. A second, related hypothesis, that the channels remain open to permit blood flow directly from the left ventricular cavity through vascular connections, has not proven valid for the infrared lasers most commonly used. A third concept, that of cardiac denervation after TMR, appeared plausible and was supported by some, albeit indirect, evidence. Hirsch and colleagues appear, after a direct assessment of cardiac nerve function, to have dismissed even this idea. The authors, drawing on experience in surgery, anesthesiology and biophysics, have provided a thorough test of the denervation concept. As with most studies, there remain some unanswered questions. For example, although the authors were careful to switch from pentothal anesthesia to 
-chloralose during the experimental procedure to minimize the confounding effect of neuronal depression, it cannot be assumed that -chloralose is without neuronal effect. In addition, it is possible that the global ventricular effects of the applied stimuli may mask regional consequences that laser treatment might most reasonably be expected to produce. The addition of a "positive control group," one in which a treatment known to impair nerve function was used, would have provided a reference for comparison. Nevertheless, the conclusion that laser treatment did not affect axonal function is difficult to dispute. So where does this "third strike" leave TMR? The lack of a proven mechanism does not preclude clinical application, but does cast doubt. Interestingly, clinical TMR has been, probably for commercial reasons, well ahead of the basic science. Again, this is not necessarily bad but, without mechanistic insight, confidence in the procedure could be undermined. So far, FDA advisory panels have stated that while they would like the mechanism issue resolved, they have not yet insisted upon having such information prior to recommendation for device approval.
It is evident that TMR is more complex than first thought, with the likelihood that multiple events and mechanisms are involved. Despite this complexity, many clinical studies have focused primarily on the assessment of angina. Although this parameter is certainly important to patients, it is a difficult one to ascribe mechanisms to. Therefore, it is perhaps no surprise that Hirsch and colleagues provided no discussion regarding the relationship between their results and anginal pain. The perception of pain and its inherent subjectivity represent difficult endpoints on which to base any concept and also highlight the need for inclusion of control groups in clinical evaluation of TMR. Although the possibility of TMR producing a placebo effect has been considered and generally discounted, reexamination of the issue is worthwhile. Bienenfeld and colleagues, in a review of cardiovascular placebo effects, reported that both improvement in exertional angina of 30% to 80%, as well as a 90–120 second increase in treadmill exercise tolerance could be expected with placebo therapy [1]. In this regard, one of the few TMR studies with a control group found that treadmill time increased after TMR, but only to the same extent as controls [2]. Nevertheless, angina was significantly reduced only with TMR. Of course, this does not rule out the possibility of TMR itself acting as a "placebo". It is worth remembering that internal mammary artery ligation was once used to treat angina, and that the pericardial abrasion studies of Beck and Leighninger resulted in more than 80% of the treated patients reporting either no or less angina after the procedure [3]. The focus on angina may reflect previous failures to demonstrate unequivocal improvements in myocardial perfusion and function. However, in light of the current study, future TMR protocols should be constructed to permit rigorous, preferably quantitative, and mechanism-based testing of new hypotheses.
The range of disciplines involved in, and indeed required for, TMR (from engineering to physiology, pathology, cardiology, surgery, etc) presents both challenges and opportunities. If difficulties in collaboration and communication can be surmounted, there is the potential for fruitful, multifaceted experiments as demonstrated by the current study. The clinical success of transmyocardial revascularization in the absence of a known mechanism provides optimism that even greater success might be achieved once the mechanism(s) are understood. Thus, although Hirsch and colleagues may have delivered a third strike, the game is not yet over.
References
This article has been cited by other articles:
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  S. Fuchs and R. Kornowski Transepicardial or transendocardial injury: controversies regarding angiogenic potential and mechanism of action Cardiovasc Res, February 16, 2001; 49(3): 582 - 587. [Full Text] [PDF]
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