Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning

We investigated the effects of the selective bradycardic agent ivabradine, an I-f channel inhibitor, on exercise- induced ischemia. and resulting myoc ardial stunning. Seven dogs were chronically instrumented to measure left v entricular (LV) wall thickening (Wth), aortic pressure and coronary blood f low (CBFv) (Doppler). Circumflex coronary artery stenosis was set up to sup press the increase in CBFv during a 10 min treadmill exercise. During exerc ise under saline, LVWth in the ischemic zone was depressed (-70 +/- 4%) and a prolonged myocardial stunning was subsequently observed. Infusion of iva bradine started before exercise significantly reduced heart rate (HR) at re st (-22 +/- 7%), during exercise (-33 4%) and throughout the recovery perio d (-21 +/- 2%). By reducing HR during exercise, ivabradine simultaneously i mproved LVWth compared with saline (14 +/- 1% versus 7 +/- 1%, respectively ) and subendocardial perfusion (microspheres). This anti-ischemic effect wa s subsequently responsible for a strong decrease in the intensity and sever ity of myocardial stunning. All these beneficial effects were abolished whe n HR reduction during exercise was suppressed by atrial pacing. Interesting ly, when ivabradine infusion was started after exercise, LVWth was still si gnificantly enhanced and myocardial stunning strongly attenuated. This dire ct effect of ivabradine on the stunned myocardium disappeared when HR reduc tion was suppressed by atrial pacing at rest. In conclusion, this study dem onstrates that ivabradine exerts an anti-ischemic effect that is responsibl e for subsequent protection against myocardial stunning. Furthermore, admin istration of ivabradine after the ischemic insult still improves LVWth of t he stunned myocardium.