Based on our study findings, the diagnostic sensitivity of DMPI is not significantly affected by the chronic consumption of beta-blockers. There is a common and overlapping sub-cellular and molecular pathways of action between dipyridamole and beta-blockers. Dipyridamole increases the endogenous concentration of adenosine, the underlying mechanism of which is inhibition of adenosine deaminase (ADA) enzyme. Adenosine in turn binds to A2 receptors and subsequently enhances the activity of its corresponding G-proteins. The cascade will eventually lead to increase in cellular concentration of cAMP, an event which leads to vasodilatation [20–24]. In atherosclerotic coronaries, vasodilatory response is restricted leading to the shift of blood to normal coronaries (steal phenomenon). This event is the rationale for using dipyridamole infusion to unveil possible myocardial ischemia [25–30]. On the other hand, beta adrenergic receptors bind to the same stimulatory G-proteins [31, 32]. Therefore, theoretically it can be judged that inhibitors of such receptors may decrease activation of the corresponding G-proteins, which eventually lead to decreased cellular concentration of cAMP and reduced response to dipyridamole infusion [17, 26, 33]. Based on these facts, others concluded that “much of the coronary vasodilation associated with hypoxia is dependent on adrenergic activation and that adenosine may only play a role in sustained hypoxic vasodilation when adrenergic receptors are intact” . Such a probable effect practically could result in reduced sensitivity of DMPI. This unpleasant outcome was supposed to be easily avoided with discontinuation of beta-blockers before stress protocol of dipyridamole infusion.
On the other hand, dipyridamole infusion causes an increase in rate-pressure product, which can be considered as one of the main explanations for dipyridamole-induced steal phenomenon. The masking effect of beta-blockade on such an index has been considered as another reason for decreased sensitivity of DMPI .
These hypotheses were supported with findings of some reports, which showed decreased sensitivity of DMPI in those patients with history of calcium channel blocker or beta-blocker treatment [34–39], although most of them were retrospective and suffered from limitations such as low sample size, lack of gold standard, lack of individual and separate evaluation of beta-blocker effect rather than combined effect of multiple anti-anginal drugs  and acute versus chronic beta blockade . Furthermore, controversies exist so far, as our study and also some of the other reports demonstrate opposite findings [14, 40–42].
According to the previous assumptions, beta-blocker withdrawal in patients with long-term beta-blockade is expected to result in restoring adrenergic activation and consequently better dipyridamole effect , rising the heterogeneity of regional perfusion between stress and rest phases, leading to better detection of reversible defects that might have been overlooked in case of ongoing beta-blocker treatment. Conversely, in our study, enduring beta-blocker treatment in the time of DMPI was associated with the detection of more irreversible perfusion defects, but its effect on the extent of reversible perfusion abnormalities were not established. This means that beta-blocker treatment may induce a reduction in dipyridamole-phase perfusion similar to the reduction in resting perfusion in the areas of stenotic coronary arteries. The effect of beta-blocker treatment with metoprolol on the coronary flow rate of patients with severe CAD was assessed in another study in which the patients underwent dipyridamole NH3-PET imaging while randomly on and off beta-blocker medications . In these patients, both resting and hyperemic blood flow in either stenotic or normal myocardial segments were decreased by beta-blocker treatment, in accordance with the finding of the present study . There are two possible explanations for these results. Adrenergic blockade may blunt the adenosine effect and coronary vasodilatation during ischemia due to a direct interference with the adenosine receptor or adenosine concentration , resulting in less contrast between resting and post-dipyridamole images of the ischemic areas, possibly causing overestimation of the fixed defects. Another possible mechanism is that the systolic pressure tends to be decreased by beta-blockade during dipyridamole stress; the driving pressure might be reduced and thereby may reduce the myocardial perfusion in stenotic areas during dipyridamole- and rest-phase imaging . Thus, beta-blocker withdrawal may represent more accurate estimation of the extent of fixed versus reversible defects.
On the other hand, the effect of continuing beta-blocker treatment on the heterogeneity of regional myocardial perfusion had no significant impact on the sensitivity of the DMPI in our study. As a result, regarding the acknowledged risks of discontinuation of anti-anginal medications before any diagnostic testing, on-medication imaging protocol may be considered adequate to reveal the presence of underlying CAD. Nevertheless, there are some inaccuracies in the estimation of myocardial defect size caused by beta-blocker treatment, e.g. overestimation in the size of fixed defects in our study as well as underestimation of dipyridamole-induced defect size in a previously reported study . Therefore, for the accurate analysis of the size and extent of fixed versus reversible myocardial defects especially in a known case of previous insult or candidates for long-term risk stratification, withholding beta-blocker treatment may be considered on a case-by-case basis.
Because of ethical considerations (unnecessary exposure to radiation, inherent risks to the stress phase of MPI-such as myocardial infarction, arrhythmia, etc.), we were unable to conduct a within-subject study to evaluate the effect of beta-blocker withdrawal on the sensitivity of DMPI in a single population of patients; however, the two groups in our study were comparable as far as the gender, age, type of radiotracer used for imaging and the extent of CAD were concerned. For future studies and to come into the conclusion that beta-blockers did not affect the sensitivity of the test using the same population with double measurement (one for continuation and the other for discontinuation) could be more justified. In this approach the potential confounder effects of baseline clinical characteristics of patients would be omitted.
Also the study was conducted in patients treated with four different beta-blocking agents. It would have been ideal to assess each beta-blocker disjointedly, but since the consumption of some kinds of beta-blockers such as carvedilol was very uncommon in our patients, a well-powered analysis of the data by considering each type of drug, individually, was unfeasible.