title: Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure.
abstract: Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs (n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 +/- 1% to 37 +/- 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 +/- 1% to 40 +/- 1% with Ran + Ena and from 34 +/- 1% to 41 +/- 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Detroit, MI, USA.
authors.forename: Sharad
authors.initials: S
authors.lastname: Rastogi
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sharov
authors.forename: Sudhish
authors.initials: S
authors.lastname: Mishra
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.forename: Brent
authors.initials: B
authors.lastname: Blackburn
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology*; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008790:Metoprolol / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D000069458:Ranolazine; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000083:Acetanilides; D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002316:Cardiotonic Agents; D010879:Piperazines; D011506:Proteins; D004656:Enalapril; D000069458:Ranolazine; D008790:Metoprolol