1205 M ore than 25 years ago, Kjekshus 1 documented the importance of heart rate (HR) in determining β-blocker efficacy in acute and long-term myocardial infarction inter- vention trials: the greater the decrease in HR, the better were short- and long-term prognosis. HR lowering became the standard by which β-blocker efficacy was assessed in the post–myocardial infarction patient population. 2 Presumably, a decrease in the double product (HR×blood pressure [BP]) by β-blockade served to reduce myocardial workload, thereby acutely diminishing infarct size and, over the long term, pre- venting remodeling of the left ventricle. Unexpectedly, in 2 recent landmark studies, HR lowering with a specific negative chronotropic drug, that is, ivabradine, confered little if any benefits in patients with coronary artery disease (CAD). 3,4 At a first glance, the absence of an effect of ivabradine in CAD seems to be a conundrum. 5 However, as Ferrari and Fox have pointed out, the role of HR (and its reduction) may differ according to the pathophysiologic set- ting. 3,4,6 Of note, HR lowering with the same drug significantly improved hospitalization rates in heart failure with reduced ejection fraction as shown in the Systolic Heart Failure I f Trial (SHIFT) study by Swedberg et al. 7 These conflicting obser- vations triggered the provocative question whether ivabradine was less effective in left ventricular systolic dysfuction of ischemic than of nonischemic origin. 7,8 A relevant aspect to consider in this context and that could at least in part explain these differing results is that HR has an important impact on central BP, particularly in hypertensive patients. 9 Indeed, the negative chronotropic effects of β-blockers (with the excep- tion of the vasodilating ones) was shown to be associated with an elevated central BP. 9–12 Because ivabradine can be consid- ered as a pure negative chronotropic agents without relevant effects on other BP regulating mechanisms, we wondered whether its relative inefficacy in CAD patients could also be related to increase of central (aortic) BP associated with HR lowering. Methods Study design and patient characteristics have been previously described. 13 Briefly, this was a prospective study in 46 patients with Abstract—Heart rate (HR) lowering by β-blockade was shown to be beneficial after myocardial infarction. In contrast, HR lowering with ivabradine was found to confer no benefits in 2 prospective randomized trials in patients with coronary artery disease. We hypothesized that this inefficacy could be in part related to ivabradine’s effect on central (aortic) pressure. Our study included 46 patients with chronic stable coronary artery disease who were randomly allocated to placebo (n=23) or ivabradine (n=23) in a single-blinded fashion for 6 months. Concomitant baseline medication was continued unchanged throughout the study except for β-blockers, which were stopped during the study period. Central blood pressure and stroke volume were measured directly by left heart catheterization at baseline and after 6 months. For the determination of resting HR at baseline and at follow-up, 24-hour ECG monitoring was performed. Patients on ivabradine showed an increase of 11 mm Hg in central systolic pressure from 129±22 mm Hg to 140±26 mm Hg (P=0.02) and in stroke volume by 86±21.8 to 107.2±30.0 mL (P=0.002). In the placebo group, central systolic pressure and stroke volume remained unchanged. Estimates of myocardial oxygen consumption (HR×systolic pressure and time- tension index) remained unchanged with ivabradine.The decrease in HR from baseline to follow-up correlated with the concomitant increase in central systolic pressure (r=-0.41, P=0.009) and in stroke volume (r=-0.61, P<0.001). In conclusion, the decrease in HR with ivabradine was associated with an increase in central systolic pressure, which may have antagonized possible benefits of HR lowering in coronary artery disease patients. Clinical Trials—URL: http://www.clinicaltrials.gov. Unique identifier NCT01039389. (Hypertension. 2016;67:1205- 1210. DOI: 10.1161/HYPERTENSIONAHA.116.07250.) Key Words: central blood pressure ■ coronary artery disease ■ heart rate ■ ivabradine ■ stroke volume ■ ventricular-vascular mismatch Received January 29, 2016; first decision February 10, 2016; revision accepted March 15, 2016. From the Department of Cardiology and Clinical Research, Inselspital, University of Bern Hospital, Bern, Switzerland (S.F.R., F.H.M., D.C., S.G., T.T., C.S.); and Department of Pharmacology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Inserm UMR 970, University Paris Descartes, Paris, France (S.L.). Correspondence to Franz H. Messerli, Department of Cardiology and Clinical Research, University of Bern Hospital, Bern, Switzerland, E-mail Messerli.f@gmail.com or Stefano F. Rimoldi, Department of Cardiology and Clinical Research, University of Bern Hospital, Bern, Switzerland, E-mail stefano.rimoldi@insel.ch Selective Heart Rate Reduction With Ivabradine Increases Central Blood Pressure in Stable Coronary Artery Disease Stefano F. Rimoldi, Franz H. Messerli, David Cerny, Steffen Gloekler, Tobias Traupe, Stéphane Laurent, Christian Seiler © 2016 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.116.07250 Clinical Trial at Universitaetsbibliothek Bern on May 26, 2016 http://hyper.ahajournals.org/ Downloaded from