How does caffeine increase exercise capacity but decrease myocardial flow reserve?

My fellow authors and I appreciate the comments expressed in Dr. Horvath’s letter, which largely claim that the sole reason for the negative results demonstrated in our study (1) relates to procedural differences between surgical versus percutaneous transmyocardial laser revascularization (TMR). Although we acknowledged in our study that full-thickness transmyocardial laser channels at surgery are indeed different from smaller non–full-thickness catheterbased transendocardial channels (1), we believe strongly that our blinded study accurately highlights the potent placebo effects in this patient population. As such, this causes us to doubt the clinical benefits referenced in the surgical TMR literature. Our reasons are as follows: 1) of the 17 surgical TMR studies cited in our study (11 observational studies and 6 randomized trials vs. “best” medical therapy), the main benefit is subjective improvement in angina class, and in most studies performing quantitative ischemia assessments (such as nuclear perfusion imaging) there were no improvements after surgical TMR. 2) Without controlling for the placebo effects, the nonblinded percutaneous TMR literature also showed the same magnitude of subjective angina improvement as seen with surgical TMR, which in our study was neutralized in the presence of a sham control group. 3) There is no plausible and scientifically creditable explanation for the anti-ischemic actions of percutaneous or surgical TMR, as the prevailing theories of patent channels, epicardial denervation, and local angiogenesis have not been validated in experimental models or in patients. To compound matters, in a retrospective analysis from the Society of Thoracic Surgeons (STS), the National Cardiac Database identified 3,717 patients at 173 U.S. hospitals who had received surgical TMR procedures over a 4-year period, and of these procedures, only 17% were TMR alone, whereas 67% were TMR coronary artery bypass surgery (CABG), which is an unapproved indication (2). Thus far, there has been a single blinded, randomized trial comparing TMR CABG versus CABG alone in 263 patients, and the clinical outcomes indicated no improvement in angina and exercise treadmill results with the combined procedure (3). Finally, based on our disquieting experiences with percutaneous TMR in our study, we would strongly urge additional validating, blinded, randomized clinical trials to examine the safety and efficacy of combined TMR CABG before widespread clinical use is advocated in the “real world.”