Adenosine and regadenoson cause an increase in heart rate (HR) during myocardial perfusion imaging (MPI). It has been shown that patients with diabetes mellitus have a blunted HR response due to cardiac autonomic dysfunction. It is not known whether the HR response is related to hyperglycemia and the metabolic syndrome (MS). HR changes were assessed in 2,000 patients (643 with diabetes mellitus [DM]) in the Adenoscan Versus Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging (ADVANCE MPI 1 and ADVANCE MPI 2) trials in relation to MS status and blood sugar level on the day of MPI. The HR response was lower in patients with MS (32.43 ± 0.52% vs 36.15 ± 0.71%, p <0.001). An increase in the number of features of MS was associated with a stepwise decrease in the HR response (-0.92% per MS criterion, p <0.05), irrespective of the presence of DM. Increasing blood sugar levels resulted in blunting of the HR response even after controlling for DM and MS (0.60 ± 0.08% per 10 mg/dl, p <0.001). MS was independently related to the HR response on top of DM, renal function, left ventricular function, gender, age, baseline HR, blood pressure, and β-blocker use. The overall model was highly associated with the HR response (p <0.001) and able to explain 30% of its variation. In conclusion, the HR response to adenosine and regadenoson is blunted in patients with hyperglycemia and in those with MS. These results suggest that factors that precede the development of DM may be associated with cardiac autonomic neuropathy and may help explain the contribution of hyperglycemia and MS to cardiovascular risk. © 2010 Elsevier Inc. All rights reserved.