ORIGINAL ARTICLE Selective Heart Rate Reduction Improves Metabolic Syndrome–related Left Ventricular Diastolic Dysfunction Nassiba Merabet, PhD,*†‡ Yuehua Fang, MD, PhD,*†‡ Lionel Nicol, PhD,*†‡§ Christelle Monteil, PhD,*‡¶ Isabelle Rémy-Jouet, PhD,*†‡ Jean-Paul Henry, BSc,*†‡ Didier Wecker, PhD,k Sabrina Le Bouter-Banon, PhD,** Jerome Roussel, PhD,** Vincent Richard, PhD,*†‡ Christian Thuillez, MD, PhD,*†‡§ and Paul Mulder, PhD*†‡§ Background: Enhanced heart rate observed in metabolic syn- drome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocar- dial O 2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown. Methods: We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg$kg 21 $d 21 ). Results: Delayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end- diastolic pressure–volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pres- sure and LV end-systolic pressure–volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glu- cose levels, and Hb1c, were never modified. Conclusions: In rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic sta- tus. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifi- cations in the myocardial structure. Key Words: diastolic function, metabolic syndrome, heart rate reduction (J Cardiovasc Pharmacol Ô 2015;66:399–408) INTRODUCTION Metabolic syndrome (MS) and/or type-2 diabetes mellitus is/are associated with an enhanced cardiovascular morbidity and mortality. 1,2 The augmentation of the latter is, at least in part, related to the development of heart failure (HF) with preserved left ventricular (LV) ejection fraction, 3 which has a mortality rate comparable to that of HF patients with reduced ejection fraction. Although major progress has been made in the past 20 years in the treatment of HF with reduced LV ejection fraction, most of these treatments show little or no efficacy in the context of HF with preserved LV ejection fraction. This might be related to the fact that the current treatments do not or only moderately attenuate LV diastolic dysfunction, that is, impaired LV relaxation, increased LV stiffness, and/or abnormal early LV filling. Increased heart rate, due to an enhanced adrenergic drive as observed in MS patients, 4 might be one of the mech- anisms implicated in the progressive diastolic LV dysfunction and vascular dysfunction observed in this disease. Indeed, we showed before that the reduction in adrenergic drive and heart rate by b-blockers, that is, nebivolol and to a smaller extent metoprolol, opposes the progression of LV diastolic dysfunc- tion, at least in part via an increased NO bioavailability together with reduced oxidative stress. 5 However, it should be stressed that after long-term b-blockade, other mecha- nisms, such as prevention of b-receptor downregulation or reduced catecholamine-induced myocardial toxicity, are potentially involved, and thus, it is not yet known whether heart rate reduction (HRR) per se opposes diastolic dysfunc- tion in MS. S38844 is a novel selective inhibitor of the car- diac pacemaker If current, or sinoatrial node modulator, which, as ivabradine, 6,7 induces a selective and dose- dependent HRR without modifying atrioventricular or intra- ventricular conduction or contractility. We used this specific heart rate–reducing agent to determine the effects of long- term selective HRR induced by If current inhibition on MS- related LV dysfunction and remodeling and on MS-related impairment of vasodilator function, together with the mecha- nisms involved. Received for publication February 3, 2015; accepted June 22, 2015. From the *Institut National de la Santé et de la Recherche Médicale U1096, Rouen, France; †Institute for Research and Innovation in Biomedicine, Rouen, France; ‡UFR de Médecine et Pharmacie, Rouen University, Rouen, France; §Plateau d’Imagerie CardioThoracique de l’Universite de Rouen, Rouen, France; ¶Equipe d’Acceuil 4651, Aliment Bioprocedes Toxicologie Environnement, Rouen, France; kBruker Biospin MRI GMBH, Ettlingen, Germany; and **Servier, Suresnes, France. Supported by a research grant of SERVIER and FEDER. Moreover, assistance of Elodie Gomez and Ji Gao and Julie Favre was gratefully acknowledged. The authors report no conflicts of interest. Reprints: Paul Mulder, PhD, INSERM U1096, UFR de Médecine et de Pharmacie, 22 Boulevard Gambetta, Rouen 76183, France (e-mail: paul.mulder@univ-rouen.fr). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. J Cardiovasc Pharmacol ä  Volume 66, Number 4, October 2015 www.jcvp.org | 399 Copyright © 201 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 5